|Ahead of print publication
Radiobiological modeling of radiation-induced acute proctitis: A single-institutional study of prostate carcinoma
Balbir Singh1, Gaganpreet Singh2, Arun Singh Oinam3, Maninder Singh4, Vivek Kumar5, Rajesh Vashistha4, Manjinder Singh Sidhu4, Ajay Katake4
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, Punjab, India
3 Department of Radiotherapy, PGIMER, Chandigarh, Punjab, India
4 Department of Radiation Oncology, Max Superspeciality Hospital, Bathinda, Punjab, India
5 Centre for Medical Physics, Panjab University, Chandigarh, Punjab, India
|Date of Submission||01-Jul-2021|
|Date of Acceptance||12-Aug-2021|
|Date of Web Publication||27-Apr-2022|
Arun Singh Oinam,
Department of Radiotherapy, PGIMER, Chandigarh - 160 012
Source of Support: None, Conflict of Interest: None
Purpose: To estimate the fitting parameters of the sigmoidal dose response (SDR) curve of radiation-induced acute proctitis in prostate cancer patients treated with intensity modulated radiation therapy (IMRT) for the calculation of normal tissue complication probability (NTCP).
Materials and Methods: Twenty-five prostate cancer patients were enrolled and evaluated weekly for acute radiation-induced (ARI) proctitis toxicity. Their scoring was performed as per common terminology criteria for 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 prostate cancer patients.
Results: ARI toxicity for rectum in carcinoma of prostate patients was calculated for the endpoint of acute proctitis. The n, m, TD50, and γ50 parameters from the SDR curve of Grade 1 and Grade 2 acute proctitis are found to be 0.13, 0.10, 30.48 ± 1.52 (confidence interval [CI] 95%), 3.18 and 0.08, 0.10, 44.37 ± 2.21 (CI 95%), 4.76 respectively.
Conclusion: This study presents the fitting parameters for NTCP calculation of Grade-1 and Grade-2 ARI rectum toxicity for the endpoint of acute proctitis. The provided nomograms of volume versus complication and dose versus complication for different grades of acute proctitis in the rectum help radiation oncologists to decide the limiting dose to reduce the acute toxicities.
Keywords: Acute radiation toxicity, common terminology criteria for adverse event, normal tissue complication probability, proctitis
|How to cite this URL:|
Singh B, Singh G, Oinam AS, Singh M, Kumar V, Vashistha R, Sidhu MS, Katake A. Radiobiological modeling of radiation-induced acute proctitis: A single-institutional study of prostate carcinoma. J Can Res Ther [Epub ahead of print] [cited 2022 Nov 29]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=344232
| > Introduction|| |
Pelvic radiation therapy has become an important component of the curative treatment of various types of malignancies. The fixed position of the rectum in the pelvis and its proximity to the prostate, cervix, and uterus make it particularly susceptible to damage to secondary radiation injury resulting in acute radiation proctitis. Acute proctitis has been attributed to radiation-induced injury to the epithelium of the rectal mucosa. This injury results in mucosal sloughing, acute inflammatory infiltrates, and increased vascular permeability leading to edema. These early changes are associated with increased bowel frequency, bowel urgency, and rectal pain. Radiation-induced damage of rectal epithelium is a widespread side effect of prostate radiotherapy, leading to pain, and weight loss. Thus, compromising the quality of life (QOL) may lead to treatment interruptions resulting in poor treatment outcomes. Acute radiation-induced (ARI) proctitis usually manifests itself during or shortly after the radiotherapy. Computation of radiobiological parameters for radiation-induced acute proctitis toxicity in radiotherapy treatment planning plays a vital role in estimating normal tissue complication probability (NTCP). The incidence of acute toxicity is common between external beam radiation therapy (EBRT) and chemotherapy. The effects of both treatment modalities are synergistic. In view of various published studies and clinical experience of radiation oncologists, normal or healthy tissues present close to the tumor receive the high doses as part of the target volume, thus producing the normal tissue toxicity., Most of the radiobiological models utilize the dose volume histograms (DVHs) data of the irradiated target and organs at risk (OAR) volumes in the treatment plan to calculate the NTCP and tumor control probability.,, 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. In the study of Emami et al., normal tissue tolerance doses were calculated for uniformly irradiated 1/3rd, 2/3rd, and the whole volume of organs using a standard fractionation scheme, i.e., 1.8 Gy to 2.0 Gy per fraction. Many radiobiological models have compiled dose tolerance data for several 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.,, In this study, ARI proctitis is considered because there is a lack of availability of data for Grade-1 and Grade-2 toxicity of rectum for nonuniform irradiation. Acute tissue toxicity in terms of radiobiological endpoints for Grade-1 and Grade-2 toxicity of rectal mucosa was investigated for the prostate cancer patients treated with intensity modulated radiotherapy therapy (IMRT) technique. The mathematical modeling of the dose-response relationship curve requires a number of parameters that can be utilized to define the dose constraints of the organ of interest for safe and well-tolerated doses. This study aims to calculate the fitting parameters corresponding to the different radiobiological endpoints of acute radiation toxicity in prostate cancer patients during EBRT and utilize these derived parameters to determine the NTCP under condition of inhomogeneous radiation.
| > Materials and Methods|| |
Twenty-five patients of prostate cancer were selected for this study, and their characteristics are shown in [Table 1]. The selected patients have only prostate primary toxicity site in pelvic cancer.
|Table 1: Patient (n=25) and tumor characteristics in patients with prostate tumors treated via intensity modulated radiation therapy|
Click here to view
Patient simulation and delineation
All prostate cancer patients followed a proper protocol of bowel emptying and bladder filling before simulation and each fraction of treatment. 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) with a slice thickness 3.75 mm. Each patient was immobilized with four clamps thermoplastic cast. All the patients were scanned from the upper border of the liver to the mid-shaft of the femur to include the primary site. The delineation of OARs, gross tumor volume, nodes (if any), and clinical target volumes namely was performed on FOCAL SIM version 5.11 (Elekta CMS, Maryland Heights, MO, USA) using RTOG guidelines of pelvic cancer, as shown in [Figure 1]. The rectum was delineated from recto-sigmoid junction to pubic symphysis. T2-weighted sequence of magnetic resonance imaging was used to better delineate the target and OARs. 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: Rectal mucosa (green color) and bladder (purple color) over the axial (top left), coronal (bottom left), sagittal (bottom right) and three-dimensional view (top right)|
Click here to view
CMS XiO (version 5.10) TPS (Elekta, Stockholm AB, Sweden) was used to create the Simultaneous Integrated Boost IMRT radiotherapy treatment plans of prostate cancer patients. Three prescription dose regimens were chosen, i.e., 70 Gy and 50.4 Gy corresponding to the planned target volume (PTV) and nodes (if any) in 28 fractions using RTOG 0415 guidelines respectively, and 75.6 Gy or 76 Gy corresponding to the PTV in 36 and 38 fractions, respectively, as shown in [Table 2]. The mean coverage of PTV and 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., 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. A pretreatment patient-specific quality assurance (passing/failure criteria) test was performed for each patient with I'mRT MatriXX having two-dimensional (2D) array of ion chamber (Scanditronix Wellhofer, Freiburg, Germany) which consists of 1020 ion chambers to verify the IMRT treatment plan's dose delivery. The gamma evaluation criterion was chosen as 3 mm for dose-to-agreement and 3% for dose difference for gamma analysis using Omni Pro IMRT verification software version 1.77.0021 (Scanditronix Wellhofer, Freiburg, Germany).
Assessment of acute radiation-induced toxicity: Proctitis
Radiation-induced acute toxicity was assessed for the radiobiological endpoint, i.e., proctitis. Mucosal reactions of the rectal mucosa were clinically evaluated by well-trained physicians/radiation oncologists. Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 was used to grade acute radiation toxicities in each patient. The entire grades are classified into five categories for toxicity assessment as shown in [Table 3]. This toxicity was documented once per week during radiation and 2 weeks after the end of the radiation therapy treatment for a total duration of 6–8 weeks.
|Table 3: Common terminology criteria for adverse events for scoring toxicity|
Click here to view
The clinical outcome of the patients having different grades of toxicity was correlated with the delivered dose during the course of radiation therapy treatment. The sigmoidal dose-response (SDR) curve fitting was performed using the data of (i) mean and partial volume doses of OARs calculated from the DVHs, (ii) the number of fractions delivered, and (iii) time of onset of the acute radiation toxicities were taken as input parameters. The radiobiological parameters n, m, TD50 and γ50 calculated from the SDR curve. The parameters: TD50 is the tolerance dose to the total organ that causes a 50% probability of complication, “n” determines the volume dependence of the complication probability, “m” defines the slope of the complication probability versus dose curve and γ50 defines the slope of SDR curve of normal tissue at 50% complication probability.,
| > Results|| |
All 25 patients who underwent radiotherapy course of treatment were clinically evaluated for the acute toxicities (during the treatment and also on a weekly basis). Their responses were recorded as per CTCAE v5 criteria. The number of patients who appeared with different grades of acute toxicity is shown in [Table 4].
Radiobiological modeling and its parameters
The change of complication probability with change in dose and volume are plotted in the form of a surface plot. [Figure 2] and [Figure 3] show the dose-response curve Grade 1 and Grade 2 of radiation-induced proctitis. In each of these figures, (i) [Figure 2]a and [Figure 3]a represents 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]b and [Figure 3]b represents the change of NTCP corresponding to the change of volume of irradiation of the OARs. (iii) [Figure 2]c and [Figure 3]c show the complication probability as a function of dose for 1/3rd, 2/3rd, and the whole volume of the OARs and showing threshold dose behavior for the NTCP (iv) [Figure 2]d and [Figure 3]d represent the surface plot of tolerance dose on one axis, partial volume on second axis against the complication probability on the third axis. The values of n, m, TD50, and γ50 parameters for Grade 1 and Grade 2 proctitis are calculated from the fitted SDR curve as shown in [Table 5].
|Figure 2: Proctitis Grade 1 Nomogram. (a) Nomogram of complication probability as a function of partial volume for partially irradiated organs at risk 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 organs at risk. (d) Surface plot of tolerance dose on one axis, partial volume on second axis against the complication probability on the third axis|
Click here to view
|Figure 3: Proctitis Grade 2 Nomogram. (a) Nomogram of complication probability as a function of partial volume for partially irradiated organs at risk 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 organs at risk. (d) Surface plot of tolerance dose on one axis, partial volume on second axis against the complication probability on the third axis|
Click here to view
|Table 5: Radiobiological parameters obtained from the sigmoidal dose response curve fitting|
Click here to view
| > Discussion|| |
It is a well-known fact that radiation therapy causes an impact on QOL. The association between the doses received by the rectal mucosa and incidence of patient-reported acute rectal mucosal toxicity in the prostate cancer patient population is still not known for Grade-1 and Grade-2 toxicity. This study has addressed this critical knowledge gap. The incidence of Grade-3 and Grade-4 of ARI proctitis was found to be low despite the usage of high radiation doses in prostate cancer patients. This is because of the use of conformal radiation technique, i.e., IMRT.
In the study of Burman et al., dose-volume parameters based on normal tissue tolerance doses were given only for 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. 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 (CRT), but there is a nonavailability of radiobiological parameters for many normal tissues which can estimate NTCP. The rectal mucosa is one of them, and their acute toxicity has been studied in the present study for the endpoint of proctitis. The tolerance doses of rectal mucosal toxicity were calculated for the reference area of 10 cm2, 30 cm2, and 100 cm2 of these organs and are similar to the methodology used in Emami et al. as tolerance dose was calculated for the skin.
Burman et al. initially attempted to determine the complication probability of acute proctitis. This model can predict the rectal toxicity for the endpoint of proctitis for Grade-3 or above. All the radiobiological parameters determined in this study were only for late radiation-induced effects. However, no radiobiological parameter and SDR curve were calculated for acute effects of radiation which can predict Grade-1, Grade-2, and above radiation-induced proctitis.
In the study of Marks et al. quantitative analysis of normal tissue effects in clinic data of dose-volume for various organs including rectum for 3D-CRT irradiation technique corresponding to late toxicity were provided but not given any radiobiological parameters which can predict ARI toxicity in the rectum for the endpoint of proctitis.
Michalski et al. had studied rectal toxicity based on dose-volume effect of the rectum. The volume receiving more than 60 Gy can produce Grade-2 or more toxicity corresponding to the endpoint of rectal bleeding. To determine these toxicity data, Lyman–Kutcher–Burman model normal tissue complication parameters were used. There are no radiobiological parameters specified in his study which can predict the Grade-1 and Grade-2 rectum toxicity for the endpoint of proctitis.
In the present study, various radiobiological fitting parameters from the SDR curve of proctitis were determined. 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 on parameter “n.” With the increase in the value of “n”, volume dependence for the occurrence of complication also increases. The value of “n” is 0.10, for grade G1 and G2 respectively, which is more than zero for both the normal tissue as shown in [Figure 2]d and [Figure 3]d. Therefore complication probability produced is having small volume dependence of the tissue being irradiated. These curves are shown in [Figure 2]a and [Figure 3]a are for G1 and G2 proctitis and representing complication probability as a function of partial volume keeping the dose constant. The SDR curves of proctitis for both grades show threshold type behavior of complication probability for any given dose. The complication probability is not varying with partial volume until a specific volume gets irradiated. At low partial volumes, the toxicity rises faster; as the dose increases, complication probability increases. As the TD50 values increase, the complication severity also increases gradually for the radiobiological endpoint for different toxicity grades.
[Figure 2]b and [Figure 3]b represent the partial volume as a function of dose, keeping the complication probability constant for proctitis for both the grades corresponding to complication probability of 5%, 20%, and 50%. As the dose is increased for a constant complication, the irradiated partial volume decreases.
The tolerance doses for 5%, 20%, and 50% complication of the irradiated tissues were calculated for whole, 2/3, 1/3 uniform organ irradiation as shown in [Figure 2]c and [Figure 3]c. For any constant partial volume of the rectum, complication probability rises as the dose is increased.
Any dose volume-related complication probabilities can be calculated using the nomogram diagram as shown in [Figure 2]d and [Figure 3]d.
The SDR curve for normal tissue is the probability of causing complications in an organ as a function of dose. 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. The slight variation in m and TD50 changes the complication probability as shown in [Figure 2]c and [Figure 3]c, representing the complication probability as a function of dose keeping the partial volume constant for whole, 2/3rd, and 1/3rd 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) small number of patients (n = 25) and a single institutional data; (ii) DVH data is used to calculate volumetric doses of OARs that lack in 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., The results of radiobiological parameters extracted from SDR curves can be used to estimate NTCP of acute proctitis in prostate cancer patients.
| > Conclusion|| |
One of the most recurring complications of prostate radiation therapy is acute proctitis, which results as a response to therapeutic management. In this single-institution cohort, the rate and severity of acute proctitis observed following IMRT are low. In this study, radiobiological parameters were derived successfully from the SDR curve for Grade-1 and Grade-2 acute proctitis of individual prostate cancer patients. These parameters can estimate the dependence of toxicity in this organ, which can predict acute proctitis in a large patient cohort. Using a nomogram of Grade-1 and Grade-2 toxicity, any reader can manually calculate the dose volume-related complication probabilities of acute proctitis. Late adverse effects in the rectal mucosa can also be examined in another study. After calculating the radiobiological parameters, it increases the clinician's confidence in making any clinical decisions during plan evaluation. In addition to it, our results need to be validated in a larger cohort of patients.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Morris KA, Haboubi NY. Pelvic radiation therapy: Between delight and disaster. World J Gastrointest Surg 2015;7:279-88.
Tabaja L, Sidani SM. Management of radiation proctitis. Dig Dis Sci 2018;63:2180-8.
Najafi M, Motevaseli E, Shirazi A, Geraily G, Rezaeyan A, Norouzi F, et al
. Mechanisms of inflammatory responses to radiation and normal tissues toxicity: clinical implications. Int J Radiat Biol 2018;94:335-56.
Serrano NA, Kalman NS, Anscher MS. Reducing rectal injury in men receiving prostate cancer radiation therapy: Current perspectives. Cancer Manag Res 2017;9:339-50.
Michalski JM, Gay H, Jackson A, Tucker SL, Deasy JO. Radiation dose – Volume effects in radiation-induced rectal injury. Int J Radiat Oncol Biol Phys 2010;76:S123-9.
Radojevic MZ, Tomasevic A, Karapandzic VP, Milosavljevic N, Jankovic S, Folic M. Acute chemoradiotherapy toxicity in cervical cancer patients. Open Med (Wars) 2020;15:822-32.
Rubin P, Cassarett GW. Urinary tract: The kidney. Clin Radiat Pathol 1968;1:293-333.
Warkentin B. Radiobiological modelling in radiation oncology. Med Phys 2008;35:1621.
Mesbahi A, Rasouli N, Mohammadzadeh M, Nasiri Motlagh B, Ozan Tekin H. Comparison of radiobiological models for radiation therapy plans of prostate cancer: Three-dimensional conformal versus intensity modulated radiation therapy. J Biomed Phys Eng 2019;9:267-78.
Oinam AS, Singh L, Shukla A, Ghoshal S, Kapoor R, Sharma SC. Dose volume histogram analysis and comparison of different radiobiological models using in-house developed software. J Med Phys 2011;36:220-9.
] [Full text]
Kehwar TS. Analytical approach to estimate normal tissue complication probability using best fit of normal tissue tolerance doses into the NTCP equation of the linear quadratic model. J Cancer Res Ther 2005;1:168-79.
Rubin P, Casarett G. Direction for clinical radiation pathology. The tolerance dose. Front Radiat Ther Oncol 1972;6:1-16.
Emami B, Lyman J, Brown A, Coia L, Goitein M, Munzenrider JE, et al.
Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys 1991;21:109-22.
Coia L, Emami B, Solin LJ, Munzenrider JE, Lyman J, Shank B, et al
. Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys 1991;21:109-22.
Mavroidis P, Pearlstein KA, Dooley J, Sun J, Saripalli S, Das SK, et al.
Fitting NTCP models to bladder doses and acute urinary symptoms during post-prostatectomy radiotherapy. Radiat Oncol 2018;13:17.
Niemierko A, Goitein M. Modeling of normal tissue response to radiation: The critical volume model. Int J Radiat Oncol Biol Phys 1993;25:135-45.
Burman C, Kutcher GJ, Emami B, Goitein M. Fitting of normal tissue tolerance data to an analytic function. Int J Radiat Oncol Biol Phys 1991;21:123-35.
Stillie AL, Kron T, Fox C, Herschtal A, Haworth A, Thompson A, et al.
Rectal filling at planning does not predict stability of the prostate gland during a course of radical radiotherapy if patients with large rectal filling are re-imaged. Clin Oncol 2009;21:760-7.
Nitsche M, Brannath W, Brückner M, Wagner D, Kaltenborn A, Temme N, et al.
Comparison of different contouring definitions of the rectum as organ at risk (OAR) and dose-volume parameters predicting rectal inflammation in radiotherapy of prostate cancer: Which definition to use? Br J Radiol 2017;90:1-12.
Gay HA, Barthold HJ, O'Meara E, Bosch WR, El Naqa I, Al-Lozi R, et al.
Pelvic normal tissue contouring guidelines for radiation therapy: A Radiation Therapy Oncology Group consensus panel atlas. Int J Radiat Oncol Biol Phys 2012;83:e353-62.
Lee WR, Dignam JJ, Amin M, Bruner D, Low D, Swanson GP, et al.
NRG oncology RTOG 0415: A randomized Phase III non-inferiority study comparing 2 fractionation schedules in patients with low risk prostate cancer. Int J Radiat Oncol Biol Phys 2015;94:3-4.
Gregoire V, Mackie TR. Dose prescription, reporting and recording in intensity-modulated radiation therapy: A digest of the ICRU Report 83. Imaging Med 2011;3:367.
Niemierko A, Goitein M. Calculation of normal tissue complication probability and dose-volume histogram reduction schemes for tissues with a critical element architecture. Radiother Oncol 1991;20:166-76.
Liu L, Meers K, Capurso A, Engebretson TO, Glicksman AS. The impact of radiation therapy on quality of life in patients with cancer. Cancer Pract 1998;6:237-42.
Delobel JB, Gnep K, Ospina JD, Beckendorf V, Chira C, Zhu J, et al.
Nomogram to predict rectal toxicity following prostate cancer radiotherapy. PLoS One 2017;12:e0179845.
Bentzen SM, Constine LS, Deasy JO, Eisbruch A, Jackson A, Marks LB, et al.
Quantitative analyses of normal tissue effects in the clinic (QUANTEC): An introduction to the scientific issues. Int J Radiat Oncol Biol Phys 2010;76:S3-9.
Marks LB, Yorke ED, Jackson A, Ten Haken RK, Constine LS, Eisbruch A, et al.
Use of normal tissue complication probability models in the clinic. Int J Radiat Oncol Biol Phys 2010;76:S10-9.
Stavreva N, Stavrev P, Warkentin B, Fallone BG. Derivation of the expressions for $γ$50 and D50 for different individual TCP and NTCP models. Phys Med Biol 2002;47:3591.
Singh G, Oinam AS, Kamal R, Handa B, Kumar V, Rai B. Voxel based BED and EQD2
evaluation of the radiotherapy treatment plan. J Med Phys 2018;43:155-61.
] [Full text]
Singh G, Kamal R, Thaper D, Oinam AS, Handa B, Kumar V, et al.
Voxel based evaluation of sequential radiotherapy treatment plans with different dose fractionation schemes. Br J Radiol 2020;93:20200197.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]