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ORIGINAL ARTICLE
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Radiobiological modeling of radiation-induced acute mucosal toxicity (oral mucositis and pharyngeal mucositis): A single-institutional study of head-and-neck carcinoma


1 Centre for Medical Physics, Panjab University, Chandigarh; Department of Radiation Oncology, Max Superspeciality Hospital, Bathinda, Punjab, India
2 Centre for Medical Physics, Panjab University; Department of Radiotherapy, PGIMER, Chandigarh, India
3 Department of Radiotherapy, PGIMER, Chandigarh, India
4 Centre for Medical Physics, Panjab University, Chandigarh, India
5 Department of Radiation Oncology, Max Superspeciality Hospital, Bathinda, Punjab, India

Date of Submission27-Mar-2021
Date of Decision11-Jun-2021
Date of Acceptance19-Jun-2021
Date of Web Publication09-Oct-2021

Correspondence Address:
Arun Singh Oinam,
Department of Radiotherapy, PGIMER, Chandigarh - 160 012,
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.jcrt_504_21

 > Abstract 


Purpose/Objective(s): This study aimed to estimate the fitting parameters of sigmoidal dose–response (SDR) curve of radiation-induced acute oral and pharyngeal mucositis in head-and-neck (H and N) cancer patients treated with Intensity Modulated Radiation Therapy (IMRT) for the calculation of normal tissue complication probability (NTCP).
Materials and Methods: Thirty H-and-N cancer patients were enrolled to model the SDR curve for oral and pharyngeal mucositis. The patients were evaluated weekly for acute radiation-induced (ARI) oral and pharyngeal mucositis toxicity, and their scoring was performed as per the common terminology criteria adverse events version 5.0. The radiobiological parameters, namely n, m, TD50, and γ50 were calculated from the fitted SDR curve obtained from the clinical data of H-and-N cancer patients.
Results: ARI toxicity for oral and pharyngeal mucosa in carcinoma of H-and-N cancer patients was calculated for the endpoint oral mucositis and pharyngeal mucositis. The n, m, TD50, and γ50 parameters from the SDR curve of Grade 1 and Grade 2 oral mucositis were found to be [0.10, 0.32, 12.35 ± 3.90 (confidence interval [CI] 95%) and 1.26] and [0.06, 0.33, 20.70 ± 6.95 (CI 95%) and 1.19] respectively. Similarly for pharyngeal mucositis, n, m, TD50, and γ50 parameters for Grade 1 and Grade 2 were found to be [0.07, 0.34, 15.93 ± 5.48 (CI. 95%) and 1.16 ] and [0.04, 0.25, 39.02 ± 9.98(CI. 95%) and 1.56] respectively.
Conclusion: This study presents the fitting parameters for NTCP calculation of Grade 1 and Grade 2 ARI toxicity for the endpoint of oral and pharyngeal mucositis. The provided nomograms of volume versus complication and dose versus complication for different grades of oral mucositis and pharyngeal mucositis help radiation oncologists to decide the limiting dose to reduce the acute toxicities.

Keywords: Acute radiation toxicity, common terminology criteria for adverse events, normal tissue complication probability, oral mucositis, pharyngeal mucositis



How to cite this URL:
Singh B, Singh G, Oinam AS, Kumar V, Vashistha R, Sidhu MS, Singh M. Radiobiological modeling of radiation-induced acute mucosal toxicity (oral mucositis and pharyngeal mucositis): A single-institutional study of head-and-neck carcinoma. J Can Res Ther [Epub ahead of print] [cited 2021 Dec 5]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=327877




 > Introduction Top


Radiation therapy is the foremost treatment modality of advanced head-and-neck (H and N) cancer due to the capability to conserve the oral cavity, pharynx, and larynx from surgical side effects related to swallowing, nerve, and speech functions.[1] However, oral mucositis and pharyngeal mucositis are common and important acute radiation-induced toxicities in patients with H-and-N cancer receiving external beam radiotherapy (EBRT). It may result in pain and weight loss leading to poor quality of life. Acute radiation mucositis (ARM) usually manifests itself during or shortly after irradiation.[2],[3] Computation of radiobiological parameters for radiation-induced acute mucosal (oral and pharyngeal mucosa) toxicity in radiotherapy treatment planning plays an important role in the estimation of normal tissue complication probability (NTCP). The incidence of acute toxicity is common between EBRT and chemotherapy. The effects of both treatment modalities are synergistic. Based on multiple established studies and clinical experience of radiation oncologists, normal or healthy tissues present close to the tumor proximity receive the same high doses as that of the target volume, thus producing the normal tissue toxicity.[4],[5],[6] Most of the radiobiological models utilize the dosimetric and volumetric data in terms of dose–volume histograms (DVHs) of the irradiated organs and tumor volumes in the treatment plan to calculate the NTCP and tumor control probability.[7],[8],[9] Rubin and Casarett initially published normal tissues and organs tolerance doses in the form of TD5/5 (5% complication in 5 years) and TD50/5 (50% complication in 5 years) for calculation of NTCP.[10] In the study of Emami, normal tissue tolerances doses for only a few selected normal organs using as a function of whole and partial organ volumes in the same form of TD5/5 and TD50/5, in these studies, doses were calculated for uniformly irradiated one-third, two-third, and whole volume of organs by using standard fractionation scheme, i.e. 1.8 Gy to 2.0 Gy/fraction.[11] Many radiobiological models have compiled dose tolerance data for a number of normal tissues/organs, but there is still a lack of clinical data for all of the tissues/organs. Moreover, radiobiological endpoints calculated in these models are derived from the clinical data related to the late toxicities of the tissues.[12],[13],[14] In this study, ARM of oral and pharyngeal mucosa is taken into consideration because there is a lack of availability of such kind of data. Acute tissue toxicity in terms of radiobiological endpoints for Grade 1 and Grade 2 toxicity (oral mucositis and pharyngeal mucositis) of oral mucosa and pharyngeal mucosa is investigated for the H-and-N cancer patients treated with intensity-modulated radiotherapy therapy (IMRT) technique.[15] The mathematical modeling of the dose–response relationship curve requires a number of parameters which can be utilized to define the dose constraints of the organ of interest for safe and well-tolerated doses.[13] The objective of this study is to calculate the fitting parameters corresponding to the different radiobiological endpoints of acute radiation toxicity in H-and-N cancer patients during EBRT.


 > Materials And Methods Top


Patient selection

Thirty patients of H-and-N cancer were selected for this study and their characteristics are shown in [Table 1]. The selected patients have a range of H-and-N primary toxicity sites which include hypopharynx, oropharynx, glottis, and others (rest of the sites).
Table 1: Patient (n=30) and tumor characteristics, in patients with head-and-neck tumors treated via intensity-modulated radiation therapy

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Patient simulation and delineation

A planning computed tomography (CT) scan of each patient was taken in a supine position using 16 slice CT scanner (Light Speed 16 Gold Seal, Wipro GE Healthcare Technologies, WI, USA). Patients were immobilized with four-clamp orfit cast. All the patients were scanned from the level of brain to thoracic vertebrae (T1–T3) levels to include the primary site. The delineation of organs at risk (OARs), neck nodes, and clinical target volumes, namely was performed on FOCAL SIM Version 5.11 (Elekta CMS, Maryland Heights, MO, USA) using RTOG guidelines of H-and-N cancer, as shown in [Figure 1].[16],[17],[18] The pharyngeal mucosa was delineated from the base of the skull to the level of cricoids cartilage and oral mucosa was delineated as the whole oral mucosal cavity lining. All CT images along with the delineated structure sets were exported to the computerized medical system (CMS) XIO version 5.10 (Elekta, Stockholm AB, Sweden) treatment planning system (TPS).
Figure 1: Delineated organs at risk: Oral mucosa (cyan color) and pharyngeal mucosa (green color) over the axial (top left), coronal (bottom left), sagittal (bottom right), and 3D view (top right)

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Treatment planning

CMS XiO version 5.10 TPS (Elekta, Stockholm AB, Sweden) was used to create the simultaneous integrated boost (SIB) IMRT radiotherapy treatment plans of the H-and-N patients. Two prescription dose regimens were chosen, i.e. 56 Gy and 66 Gy corresponding to the neck nodes and PTV in 33 fractions, respectively, and 56 Gy and 70 Gy corresponding to the neck nodes and PTV in 35 fractions, respectively, as shown in [Table 2].[19],[20] The mean coverage of PTV and neck nodes by 95% of the prescribed dose was chosen as a plan evaluation parameter according to the International Commission on Radiation Units and Measurements 83.[21] All IMRT plans were made with nine fields of 6 MV X-rays beam with step and shoot delivery technique using superposition algorithm having segmentation method of smart sequencing and minimum segment area of 2 cm2 for Elekta (Synergy Platform) linear accelerator equipped with 40 pairs of multileaf collimators, and grid size of 2 mm was chosen for the dose calculation. To verify the IMRT treatment plan's dose delivery, a pretreatment patient-specific quality assurance (passing/failure criteria) procedure was performed for each patient with OmniPro IMRT verification software version 1.77.0021 using a 2D array of ion chamber I'mRT MatriXX (Scanditronix Wellhofer, Freiburg, Germany) consists of 1020 ion chambers. The gamma evaluation criterion was chosen as 3 mm for a dose to agree and 3% for a dose difference.
Table 2: Dose–volume constraints for head-and-neck cancer patients

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Assessment of acute radiation toxicities: Oral mucositis and pharyngeal mucositis

Radiation-induced acute toxicities were assessed for both of the radiobiological endpoints, i.e. oral mucositis and pharyngeal mucositis. These toxicities were scored once per week and were also taken before, during, and 2 weeks after the end of the radiation therapy treatment for a total duration of 7 weeks. Mucosal reactions of the oral cavity and pharyngeal mucosa were clinically assessed by well-trained physicians/radiation oncologists.

Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 was used for grading of acute radiation toxicities in each patient.[22] The entire grades were classified into five categories for toxicity assessment, as shown in [Table 3].
Table 3: Common Terminology Criteria for Adverse Events for scoring toxicity

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Mathematical modeling

The clinical outcome of the patients having different grades of toxicity was correlated with the delivered dose during the course of radiation therapy treatment. To fit the sigmoidal dose-response curve (SDR), the data of mean and partial volume doses derived from the DVHs and fractions given, as well as the time of onset of acute radiation toxicities, were used. The radiobiological parameters n, m, TD50 and γ50 calculated from the SDR can also be utilized to calculate the NTCP of oral and pharyngeal mucosa.


 > Results Top


All 30 patients underwent radiotherapy course of treatment were clinically evaluated for the acute toxicities (during the treatment and also on weekly basis) and their responses were recorded as per the CTCAE criteria. The number of patients appeared with different grades of acute toxicity is shown in [Table 4].
Table 4: Assessment of patients for acute radiation toxicity

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Radiobiological modeling and its parameters

The change of complication probability with change in dose and volume was plotted in the form of surface plot. [Figure 2], [Figure 3], [Figure 4], [Figure 5] show the dose–response curve of Grade 1 and Grade 2 of oral and pharyngeal mucositis. In each of these figures, (i) [Figure 2], [Figure 3], [Figure 4], [Figure 5] (a) represent the nomogram of NTCP and volume of the partially irradiated OARs for three different tolerance doses corresponding to the 5%, 20%, and 50% complication; (ii) [Figure 2], [Figure 3], [Figure 4], [Figure 5] (b) represent the change of NTCP corresponding to the change of volume of irradiation of the OARs; (iii) [Figure 2], [Figure 3], [Figure 4], [Figure 5] (c) show the complication probability as a function of dose for one-third, two-third, and whole volume of the OARs and showing threshold dose behavior for the NTCP; (iv) [Figure 2], [Figure 3], [Figure 4], [Figure 5] (d) represent the nomogram of physical dose on x-axis and partial volume on y-axis against the complication probability on the z-axis.
Figure 2: Oral Mucositis Grade 1 nomogram, (a) Nomogram of complication probability as a function of partial volume for partially irradiated OAR for three different tolerance doses, (b) Nomogram of partial volume as a function of dose for 5%, 20% and 50% complication, (c) Nomogram of complication probability as a function of dose for 1/3rd, 2/3rd and whole volume of the OAR, (d) Surface plot of tolerance dose on one axis, partial volume on second axis against the complication probability on the third axis

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Figure 3: Oral Mucositis Grade 2 nomogram, (a) Nomogram of complication probability as a function of partial volume for partially irradiated OAR for three different tolerance doses, (b) Nomogram of partial volume as a function of dose for 5%, 20% and 50% complication, (c) Nomogram of complication probability as a function of dose for 1/3rd, 2/3rd and whole volume of the OAR, (d) Surface plot of tolerance dose on one axis, partial volume on second axis against the complication probability on the third axis

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Figure 4: Pharyngeal Mucositis Grade 1 nomogram, (a) Nomogram of complication probability as a function of partial volume for partially irradiated OAR for three different tolerance doses, (b) Nomogram of partial volume as a function of dose for 5%, 20% and 50% complication, (c) Nomogram of complication probability as a function of dose for 1/3rd, 2/3rd and whole volume of the OAR, (d) Surface plot of tolerance dose on one axis, partial volume on second axis against the complication probability on the third axis

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Figure 5: Pharyngeal Mucositis Grade 2 nomogram, (a) Nomogram of complication probability as a function of partial volume for partially irradiated OAR for three different tolerance doses, (b) Nomogram of partial volume as a function of dose for 5%, 20% and 50% complication, (c) Nomogram of complication probability as a function of dose for 1/3rd, 2/3rd and whole volume of the OAR, (d) Surface plot of tolerance dose on one axis, partial volume on second axis against the complication probability on the third axis.

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The n, m, TD50, and γ50 parameters for Oral- and Pharyngeal mucositis of Grade 1 and Grade 2 toxicity were calculated from the fitted SDR curve as shown in [Table 5].
Table 5: Radiobiological parameters obtained from the sigmoidal dose–response curve fitting

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 > Discussion Top


It is well-known fact that radiation therapy causes an impact on quality of life.[23] The association between the doses received by the oral and pharyngeal mucosa and incidence of patient-reported acute (oral and pharyngeal) mucosal toxicity in H-and-N cancer patient population is still not known for Grade 1 and Grade 2 toxicity. This study has addressed this important knowledge gap. The incidence of Grade 3 and Grade 4 of acute mucositis toxicity (AMT) was found to be low despite the usage of high radiation doses in H-and-N cancer patients. This is because of the usage of conformal radiation dose delivery technique, i.e. IMRT.

In the study of Burman et al., dose–volume parameter-based normal tissue tolerance doses were given only for a few number of organs for different radiobiological endpoints and all these radiobiological endpoints were calculated based on the 2D radiation delivery technique for late tissue toxicity.[15] However, these dose–volume parameters and their associated normal tissue toxicity data are revised with the availability of recent clinical data and advanced radiotherapy techniques like conformal radiotherapy.[20] Still, there is unavailability of radiobiological parameters for oral and pharyngeal mucosa organs which can be used to estimate NTCP. To bridge this gap, in this study, tolerance doses of oral and pharyngeal mucosa toxicity are calculated for a reference area of 10 cm2, 30 cm2, and 100 cm2 similar to the methodology used for calculation of skin toxicity in the study Burman et al.[15]

In the study of Dean et al., functional data analysis approach was used for determining the complication probability of acute oral mucosa and pharyngeal mucosa toxicity of Grade 3 and above.[24] In the study of Strigari et al., Grade 3 or above acute mucosal toxicity was calculated based on various radiation treatment schedules which were classified as tolerable and intolerable AMT.[25]

Rancati et al. studied the radiobiological endpoints for larynx and pharynx OARs with the help of DVH data. These radiobiological endpoints were found to be laryngeal edema, laryngeal dysfunction for larynx, and dysphagia for pharynx. CTCAE grading was used in this study to assess the acute toxicity, similar to our study, but pharyngeal mucositis and oral mucositis were not considered.[26]

In the study of Marks et al., an upgradation over the tolerance doses for 18 organs (given in the Emami et al. study) was provided based on the conventionally fractionated regimen using conventional techniques only which may or may not be applicable to other advanced techniques.[27] The radiobiological endpoints for the pharynx and larynx organs were given as symptomatic dysphagia and aspiration, respectively. However, this study did not consider the pharyngeal and oral mucositis endpoints.

Brodin and Tomé had further investigated the acute toxicity of pharyngeal constrictor and larynx OARs for H-and-N cancer patients using advanced radiotherapy techniques i.e. IMRT. The radiobiological endpoints reported in this study were oral mucositis and dysphagia using CTCAE v. 3.0 grading criteria, but the radiobiological parameters for NTCP calculation were not provided for the different grades of toxicity related to these OARs.[28]

In the present study, various radiobiological fitting parameters from the SDR curve of oral and pharyngeal mucosa are determined using mathematical modeling and are different from the above-mentioned studies. The parameter “n” value is specifically unique for each organ which describes the volumetric dependence of the dose–response relationship. The complication probability curves for a tissue depend upon parameter “n.” With the increase in the value of n, volume dependence for the occurrence of complication increases. The calculated values of “n” are 0.10, 0.06 for G1 and G2 oral mucositis and 0.07, 0.04 for G1 and G2 pharyngeal mucositis respectively, which is more than zero for both the normal tissue, as shown in [Figure 2], [Figure 3], [Figure 4], [Figure 5](d). Therefore, complication probability produced is having small volume dependence of the tissue being irradiated. [Figure 2], [Figure 3], [Figure 4], [Figure 5](a) depict complication probability as a function of partial volume while maintaining the dose constant for G1 and G2 oral mucositis and pharyngeal mucositis, respectively. Both the toxicity curves do not show any threshold-type behavior for complications of any given dose. At low partial volumes, the toxicity rises faster, as the dose increases, complication probability increases, and beyond a certain dose complication probability becomes saturated. As the TD50 values increase, the severity of complication also increases gradually for each radiobiological endpoint for different toxicity grades.

[Figure 2], [Figure 3], [Figure 4], [Figure 5](b) represent the partial volume as a function of dose keeping the complication probability constant for oral mucositis and pharyngeal mucositis for both the grades corresponding to complication probabilities of 5%, 20%, and 50%, respectively. As the dose is increased for constant complication, the irradiated partial volume decreases.

The tolerance doses for 5%, 20%, and 50%, respectively, complication of the irradiated tissues were calculated for whole, two-third, and one-third uniform organ irradiation, as shown in [Figure 3], [Figure 4], [Figure 5](c). Any dose–volume-related complication probabilities can also be calculated using the nomogram diagram showing in [Figure 2], [Figure 3], [Figure 4], [Figure 5](d).

The SDR curve for normal tissue is the probability of causing complications in an organ as a function of dose.[29] The dose at which 50% response probability is achieved is TD50, and γ50 is the slope normalized at 50% complication for a given dose. The parameter m determines the slope of the curve for complication probability as a function of dose.[15] The small variation in the m and TD50 changes the complication probability, as shown in [Figure 2], [Figure 3], [Figure 4], [Figure 5](c), representing the complication probability as a function of dose keeping the partial volume constant for whole, two-third, and one-third volume of irradiation. As the dose is increased, complication probability is also increased for any fixed irradiated partial volume.

This study is limited to (i) a small number of patients (n = 30) and a single institutional data; (ii) dose–volume histogram data are used to calculate volumetric doses of OARs that lack spatial information. Voxel-based methods can be effective to evaluate the spatial radiobiological response of the OARs which is beyond the scope of this study.[30],[31],[32] However, the results of radiobiological parameters which are extracted from SDR curves can be used to estimate NTCP of oral and pharyngeal mucosa in H-and-N cancer patients for any treatment schedules.


 > Conclusion Top


In this study, radiobiological parameters were derived successfully from SDR curve for Grade-1 and Grade-2 acute oral and pharyngeal mucosal toxicity of individual H-and-N cancer patients. These parameters can be used to estimate the dependence of toxicity in these organs and have the potential to predict the AMT in large patient cohort. By using nomogram of Grade1 and Grade 2, any reader can manually find the dose–volume-related complication probabilities of acute oral mucositis and pharyngeal mucositis. After calculating the radiobiological parameter, it increases the confidence of the clinicians in taking any clinical decisions during plan evaluation. In addition, our results need to be validated in a larger cohort of patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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