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New dosimetric parameters to predict ano-rectal toxicity during radiotherapy treatment

      Highlights

      • Radiotherapy is essential in the treatment of locally advanced rectal cancer.
      • Side effects of radiotherapy have a great effect on quality of life.
      • D98% of the wall of lower ano-rectum < 33.5 Gy is a predictive parameter of grade 2 acute toxicity.
      • D98% of the wall of lower ano-rectum < 25 Gy is a predictive parameter of grade 1 or superior acute proctitis.

      Abstract

      Purpose

      Radiotherapy is essential in the treatment of locally advanced rectal cancer. Side effects of radiotherapy in the treatment of rectal cancer have a great effect on quality of life. The aim of this retrospective study is to evaluate the correlation between dosimetric parameters and acute toxicity in rectal cancer patients.

      Methods

      We analyzed the Dose Volume Histogram parameters for both the target structures and the Organs at risk of 89 patients. A dedicated statistical analysis was performed for all the acute toxicities showing a frequency rate higher than 20%.
      A linear logistic regression model was elaborated using the variable showing the highest level of significance at the univariate analysis.

      Results

      The occurrence of proctitis was significantly correlated with three dosimetric parameters: D98% of low ano-rectum, D98% and Dmean of low ano-rectum wall.
      A predictive linear logistic regression model reports that the D98% of the wall of the low ano-rectum must be < 38.5 Gy to decrease the rate of proctitis.
      A general analysis on grade 2 acute toxicity occurrence reported that it was correlated with D98% of low ano rectum.

      Conclusions

      Two dose constraints were elaborated: D98%<33.5 Gy for low ano rectum to prevent grade 2 acute toxicity and D98%<25 Gy for low ano-rectum wall to prevent proctitis (grade 1 or superior).

      Keywords

      Introduction

      Colorectal carcinoma is the third most common malignancy, with rectal carcinoma accounting for almost one-third of colorectal carcinomas [
      • Bray F.
      • Ferlay J.
      • Soerjomataram I.
      • Siegel R.L.
      • Torre L.A.
      • Jemal A.
      Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
      ].
      In Italy colorectal cancers are absolutely the most frequent (13% of new cancers diagnosed per year in both sexes) and in particular they represent the third most frequent neoplasia in men (after prostate and lung cancer) and the second in women (after breast cancer), in the last 10 years in Italy there has been a reduction in both the incidence and the mortality from rectal cancers in both sexes [

      Guida L. NEOPLASIE DEL RETTO E ANO 2020:474.

      ].
      The improvements in the treatment of rectal cancer derived from a multimodal approach [
      • Fokas E.
      • Glynne-Jones R.
      • Appelt A.
      • Beets-Tan R.
      • Beets G.
      • Haustermans K.
      • et al.
      Outcome measures in multimodal rectal cancer trials.
      ]. Surgery, radiotherapy (RT) and systemic therapy combine to achieve the goal of cure.
      During the latest decades, neoadjuvant RT with or without concomitant chemotherapy (CHT) followed by Total Mesorectal Excision (TME) has become the gold standard for locally advanced rectal cancer (cT3-4 and/or N1-2) treatment resulting in a significant improvement of local control [
      • Chiloiro G.
      • Boldrini L.
      • Meldolesi E.
      • Re A.
      • Cellini F.
      • Cusumano D.
      • et al.
      MR-guided radiotherapy in rectal cancer: First clinical experience of an innovative technology.
      ].
      Considering the improvement in local control reached with neoadjuvant treatments and surgical TME technique, the new priority now is the reduction of treatment-related side-effects and postoperative complications.
      In order to optimize the treatment, CHT can be administered either before or after neoadjuvant RT, referred to as Total Neoadjuvant Therapy (TNT) that is a new promising strategy in locally advanced rectal cancer [
      • Roeder F.
      • Meldolesi E.
      • Gerum S.
      • Valentini V.
      • Rödel C.
      Recent advances in (chemo-)radiation therapy for rectal cancer: a comprehensive review.
      ,
      • Kasi A.
      • Abbasi S.
      • Handa S.
      • Al-Rajabi R.
      • Saeed A.
      • Baranda J.
      • et al.
      Total Neoadjuvant Therapy vs Standard Therapy in Locally Advanced Rectal Cancer: A Systematic Review and Meta-analysis.
      ].
      Within the analysed cohort, patients underwent the following treatments according to internal institutional guidelines:
      • simultaneous RT and chemotherapy (CRT) long course, which is indicated in both cT2-3 N0 of the low rectum to avoid abdominal perineal amputation with permanent ostomy and allow sphincter preservation and in cT3-4 N0-2 M0 rectal cancers.
      • exclusive RT short course in cT3 N0 M0 medium–high rectal cancers and in T3-T4 N0-N2 when there are absolute contraindications to CHT.
      Postoperative CRT may be offered to avoid local recurrence in patients with high risk histology features who have not received preoperative CRT [

      2014-La-radioterapia-tumori-gastrointest-scaricabile.pdf n.d.

      ]. Therefore, in patients with rectal cancer, RT can be used for both neoadjuvant and adjuvant purposes. Neoadjuvant treatment is superior in terms of treatment compliance, toxicity and down-staging while adjuvant treatment allows for better selection of patients based on pathologic stage, although it might have greater toxicity. However, both approaches have similar rates of distant recovery and overall survival [

      2014-La-radioterapia-tumori-gastrointest-scaricabile.pdf n.d.

      ,
      • Sauer R.
      • Liersch T.
      • Merkel S.
      • Fietkau R.
      • Hohenberger W.
      • Hess C.
      • et al.
      Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years.
      ].
      Experiences reported in literature show a relationship between radiation treatment and adverse effects that might affect the organs at risk (OARs), which are diarrhea, cystitis, perineal dermatitis, genitourinary dysfunction [

      Joye I, Haustermans K. Early and late toxicity of radiotherapy for rectal cancer. Recent Results Cancer Res Fortschritte Krebsforsch Progres Dans Rech Sur Cancer 2014; 203:189–201. Doi: 10.1007/978-3-319-08060-4_13.

      ,
      • Jankarashvili N.
      • Kakhadze S.
      • Topeshashvili M.
      • Turkiashvili L.
      • Tchiabrishvili M.
      Neoadjuvant volumetric modulated arc radiochemotherapy with a simultaneous integrated boost technique compared to standard chemoradiation for locally advanced rectal cancer.
      ].
      Side effects of radiotherapy in the treatment of rectal cancer have a great effect on quality of life and play an important role in the well-being of the patients [
      • Fokas E.
      • Glynne-Jones R.
      • Appelt A.
      • Beets-Tan R.
      • Beets G.
      • Haustermans K.
      • et al.
      Outcome measures in multimodal rectal cancer trials.
      ].
      The aim of this retrospective study is to evaluate the correlation between dosimetric parameters and acute toxicity in rectal cancer patients.

      Materials and methods

      Patients characteristics

      We performed a retrospective analysis of 89 patients with rectal cancer, treated in our center from 01/01/2015 to 31/05/2021 (Table 1).
      Table 1Patients Characteristics.
      Mean age at diagnosis68,3
      Sex (n. pt)
      Male47
      Female42
      Clinical stage (n. pt)
      II33
      III46
      IV10
      n. pt (number of patients).
      The mean age at the time of treatment was 68.3 years (range 43 to 88 years), 42 were females and 47 males. Every patient was studied with endoscopy procedures, biopsy and magnetic resonance imaging (MRI) and underwent thoracic and abdominal computed tomography (CT) and/or positron emission tomography (PET) for routine disease staging. Histology for all patients was compatible with adenocarcinoma. Rectal cancer stage ranged from stage II to stage IVa according to the 7th edition of the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) staging system [
      • Edge S.B.
      • Compton C.C.
      The American Joint Committee on Cancer: the 7th Edition of the AJCC Cancer Staging Manual and the Future of TNM.
      ]. Specific informed consent was administered to all patients according to internal protocols.
      Hygienic advices were given to the patient prior to RT course start and appropriate support therapy such as probiotics and simethicone to reduce abdominal distention as well as daily applications of skin protecting cream to prevent skin erythema were routinely prescribed.
      During the treatment, the patients were examined weekly and blood tests were done every 7 days. To evaluate the toxicity we used the Common Terminology Criteria for Adverse Events (CTCAE) scale version 4.0 from 2015 to 2017 while we used CTCAE scale version 5.0 to evaluate the side effects presented by our patients from 2018 [

      Common Terminology Criteria for Adverse Events (CTCAE) 2009:79.

      ,

      Common Terminology Criteria for Adverse Events (CTCAE) 2017:155.

      ].

      Treatment

      67 patients underwent neoadjuvant RT and 22 patients underwent adjuvant RT (three patients had undergone an abdomino-perineal resection, 16 patients received a low anterior resection, 1 had a TME and 2 had a Hartman surgery). All patients were simulated in the supine position and immobilized to the bed treatment with the Combifix™, a baseplate system providing enhanced positioning for the pelvic region. The simulation CT was acquired with 2.5 mm thick slice, 20–30 min after drinking 500 ml of water to fill the bladder. Setup marks were drawn on the skin of the patients after laser alignment. About contouring in 2015 the clinical target volume (CTV) of the pelvis was contoured according to “La Radioterapia dei Tumori Gastrointestinali-Indicazioni e Criteri Guida 2014” [

      2014-La-radioterapia-tumori-gastrointest-scaricabile.pdf n.d.

      ] while from 2016 CTVpelvis was contoured according to “Rectal cancer guidelines” published on Radiotherapy and Oncology [
      • Valentini V.
      • Gambacorta M.A.
      • Barbaro B.
      • Chiloiro G.
      • Coco C.
      • Das P.
      • et al.
      International consensus guidelines on Clinical Target Volume delineation in rectal cancer.
      ]. The CTVboost was defined as the tumor bed identified through the fusion of MRI images with the images of our simulation CT or through the visualization of the surgical alteration. The planning target volume (PTV) of pelvis and of boost were created by adding an isotropic 8 mm margin expansion to CTVpelvis and CTVboost respectively. The OARs (bladder, bowel bag, bowel loops, femoral heads) were delineated according to RTOG guidelines [
      • Gay H.A.
      • Barthold H.J.
      • O’Meara E.
      • Bosch W.R.
      • El Naqa I.
      • Al-Lozi R.
      • et al.
      Pelvic Normal Tissue Contouring Guidelines for Radiation Therapy: A Radiation Therapy Oncology Group Consensus Panel Atlas.
      ]; anorectum was outlined from the anal margin (from the level of the ischial tuberosities) extending cranially up to 7 cm; the wall of the low ano-rectum, contoured with a thickness of about 3 mm, it was cropped to contoured Gross Tumor Volume (GTV) on T2-weighted sequences of co-registered MRI. [
      • Tucker S.L.
      • Dong L.
      • Cheung R.
      • Johnson J.
      • Mohan R.
      • Huang E.H.
      • et al.
      Comparison of rectal dose–wall histogram versus dose–volume histogram for modeling the incidence of late rectal bleeding after radiotherapy.
      ,
      • Rasmussen S.N.
      • Riis P.
      Rectal wall thickness measured by ultrasound in chronic inflammatory diseases of the colon.
      ].
      All treatments were carried out on a Linac Synergy® (Elekta, Stockholm, Sweden). This Linac is equipped with an 80-leafs multi-leaf collimator and a kilovolt Cone Beam (kV CBCT) as on-board imaging.
      Twenty two patients underwent adjuvant treatment. The prescribed RT dose was between 39.6 and 45 Gy to PTVpelvis and between 46.8 and 55 Gy to PTVboost according to tumor stage as for international guidelines [
      • Benson A.B.
      • Venook A.P.
      • Bekaii-Saab T.
      • Chan E.
      • Chen Y.-J.
      • Cooper H.S.
      • et al.
      Rectal Cancer, Version 2.2015.
      ].
      Following internal protocols, 16 patients carried out concomitant CHT with Capecitabine, 3 patients with Capecitabine and Oxaliplatinum (XELOX), 2 patients with 5-Fluorouracil (5FU) and 1 patient did not perform CHT due to renal insufficiency. 67 patients underwent neoadjuvant treatment, different dose/fraction settings were used for these patients; 6 patients underwent short course RT with 25 Gy in 5 daily fractions, 61 patients underwent long course CRT with Capecitabine [

      2014-La-radioterapia-tumori-gastrointest-scaricabile.pdf n.d.

      ] and their prescribed RT dose was between 45 and 50.4 Gy to PTVpelvis and between 50.4 and 55 Gy to PTVboost.
      As regards the RT technique, in 2015 the treatment plans were realized in 3-Dimensional Conformal RT(3D-CRT), later from 2016 to 2020 the treatment plans were realized in Volumetric Modulated Arc Therapy (VMAT) and since 2021 the treatment plans were realized using simultaneous integrated boost (VMAT/SIB) (Table 2).
      Table 2Treatment.
      Neoadjuvant RTAdjuvant RT
      n. pt6722
      Dose
      Dosepelvis (range) Gy45 – 50,439,6 – 45
      Doseboost (range) Gy50,4 – 5546,8 – 55
      Dose short course Gy25/
      Technique (n. pt)
      3D-CRT83
      VMAT4719
      VMAT/SIB12/
      CHT (n. pt)
      Capecitabine6116
      XELOX/3
      5FU/2
      No CHT61

      Dosimetric analysis

      We analysed the Dose Volume Histogram (DVH) parameters for both the target structures and OARs (bladder, bowel bag, bowel loops, anorectum, rectal wall).
      All the treatment plans were optimized to ensure the respect of the following dose objectives related to the target structures: V95% > 95% and V107% <5%.
      As for OARs, we collected the maximum dose to bladder, the volume of bowel bag receiving 45 Gy (V45Gy), the volume of bowel loops receiving 15 Gy and 30 Gy (V15Gy and V30Gy) [

      2014-La-radioterapia-tumori-gastrointest-scaricabile.pdf n.d.

      ]. Lastly, the following parameters were collected for low ano-rectum and corresponding wall low ano-rectum Dmax, Dmean, D0,2cc, D1cc, D2cc, D5cc, D2%, D50%, D98%, V20Gy, V28Gy, V35Gy, V38Gy, V40Gy.
      A comprehensive database including dosimetric data, clinical information at the diagnosis and acute gastrointestinal toxicities was created. A dedicated statistical analysis was performed for all the acute toxicities showing a frequency rate higher than 20%.
      A comprehensive analysis was also performed considering any grade 2 acute toxicity as adverse event, independently by the type of toxicity observed.
      In particular, the ability of each clinical and dosimetric parameter in predicting the acute toxicity occurrence after RT was assessed at the univariate analysis by considering the Wilcoxon Mann Whitney (WMW) test or the t-test, depending on the normality of data distribution, which was previously evaluated using the Shapiro-Wilk test [

      Taylor J. Introduction to Error Analysis, the Study of Uncertainties in Physical Measurements, 2nd Edition. Publ Univ Sci Books 648 Broadway Suite 902 N Y NY 10012 1997; 1997.

      ].
      A linear logistic regression model was elaborated using the dosimetric variable showing the highest level of significance at the univariate analysis.
      The predictive performance of the model elaborated was evaluated using the area under the Receiver Operating Characteristic (ROC) curve (AUC), with the 95% confidence intervals calculated using the bootstrap method with 2000 iterations [

      International Commissioning on Radiation Units and Measurements. Receiver Operating Characteristic (ROC) Analysis in Medical Imaging. ICRU Report 79; 2008.

      ].
      The best cut-off threshold was identified maximizing the Youden Index (J), and values of sensitivity and specificity at the best threshold were calculated [
      • Ruopp M.D.
      • Perkins N.J.
      • Whitcomb B.W.
      • Schisterman E.F.
      Youden Index and Optimal Cut-Point Estimated from Observations Affected by a Lower Limit of Detection.
      ].
      A dynamic nomogram was finally elaborated, and a dose constraint was calculated considering as acceptable an occurrence probability lower than those observed in the clinical cohort.
      The whole statistical analysis was performed using R software (version 3.6.1, Wien Austria) and dedicated packages [
      • Robin X.
      • Turck N.
      • Hainard A.
      • Tiberti N.
      • Lisacek F.
      • Sanchez J.-C.
      • et al.
      pROC: an open-source package for R and S+ to analyze and compare ROC curves.
      ].

      Results

      Patient cohorts and acute toxicities

      All the patients completed the treatment with moderate/good compliance and without interruptions. Analysis was focused on 84 patients, as 5 patients were lost to follow-up.
      In terms of acute toxicity diarrhea occurred in 29 patients (34.5%) proctitis in 23 patients (27.3%). AS for acute GU toxicity, dysuria occurred in 18 patients (21.4%), urinary frequency in 2 patients (2.2%) while urinary tract pain was shown in 9 patients (10.7%). Anemia occurred in 8 patients (9.5%) while 3 patients (3.6%) showed pelvic pain. Table 3 reports the data regarding acute toxicity. All the adverse effects observed were classified as grade 1–3 on the CTCAE (version 5) scale.
      Table 3Acute Toxicity.
      n. pt%
      Diarrhea2932,6
      Proctitis2325,8
      Dysuria1820,2
      Urinary tract pain910,1
      Anemia88,9
      Pelvic pain33,4
      Urinary frequency22,2
      Considering only acute toxicities with grade 2 or 3, a total of 21 adverse events were observed with an occurrence rate of 25%. As regards the analysis of single acute toxicities, we analysed the most frequent ones, which were diarrhea, proctitis and dysuria.
      Grade 1 diarrhea occurred in 22 patients, grade 2 in 6 patients and grade 3 in 1 patient. Grade 1 proctitis occurred in 16 patients, grade 2 in 5 patients and grade 3 in 2 patients.
      Acute dysuria occurred in 18 patients accounting for a 20.2% rate.
      Table 3 resumes data of acute toxicities rates.
      No significant correlation with the variables collected in the database was observed with regards of diarrhea and dysuria.
      Significant parameters were found for grade 2 acute toxicities and proctitis, so two predictive models were elaborated considering dosimetric parameters for such toxicities.

      Predictive model for grade 2 acute toxicities

      As regards the presence of grade 2 toxicities, a significant correlation was observed with two clinical parameters (age and sex with p equal to 0.030 and 0.045 respectively), one technical parameter (type of technique, p = 0.03) and one dosimetric parameter (D98% of low rectum, p = 0.043).
      Grade 2 toxicities resulted to be less frequent in men, younger than 58 years and treated with IMRT technique.
      A linear logistic regression model was elaborated to correlate the D98% of low rectum and the probability of observing a grade 2 acute toxicity.
      The mathematical formulation of the predictive model was the follows:
      lnpx1-px=ax+b


      where p(x) is the probability of grade 2 toxicity, x was the D98% of low rectum, a was equal to 0.02 ± 0.01 Gy−1 and b to −1.92 ± 0.54.
      At the best cut-off value (30%) corresponding to a value of Youden Index of 0.30, the predictive model exhibits a specificity of 73% and a sensitivity of 57%. The ROC curve of the model has an AUC of 0.65 (0.50–0.79 as 95% confidence interval) and it is reported in Fig. 1. To reduce the probability of grade 2 acute toxicities lower than 25% a D98% of low rectum lower than 35 Gy has to be maintained.
      Figure thumbnail gr1
      Fig. 1ROC curve of the predictive model elaborated for grade 2 toxicities with the 95% confidence intervals depicted in dash lines.
      Fig. 2 reports the probability to suffer from grade 2 toxicity l in function of the D98% of the low ano-rectum.
      Figure thumbnail gr2
      Fig. 2Histogram of the probability of grade 2 toxicities in function of D98% of low ano rectum.

      Predictive model for proctitis

      Given the statistically significant results obtained, we focused our attention on the statistical analysis of the “proctitis” parameter to find a predictive model for this event in patients being treated for rectal cancer.
      The occurrence of proctitis was significantly correlated with three dosimetric parameters: D98% of low ano-rectum (p = 0.003), D98% and Dmean of low ano-rectum wall (p = 0.005 and p = 0.01 respectively).
      At the correlation analysis performed using Pearson Correlation Coefficient, the most significant three dosimetric significant parameters resulted to be correlated among each other with correlation coefficients always higher than 0.5 (minimum value between D98% of low ano rectum and mean dose of low rectal wall equal to 0.58).
      The predictive model related to proctitis considers the D98% of low rectum wall as variable, with a parameter equal to 0.04 ± 0.01 Gy−1 and b to − 2.55 ± 0.65. At the best cut-off value (31%) corresponding to a value of Youden Index of 0.40, the predictive model exhibits a specificity of 69% and a sensitivity of 73%. (Table 4).
      Table 4Elaborated predictive model data.
      SensitivitySpecificityThresholdJ_indexAUCLow_AUCHigh_AUC
      Training72.7272769.354840.3351320.420821171.810850.59093630.8452807
      Fig. 3 reports the ROC curve of the predictive model elaborated considering the D98% of low ano-rectal wall as variable and the occurrence of proctitis as outcome: the AUC was equal to 0.72, with a 95% confidence interval ranging from 0.59 to 0.84.
      Figure thumbnail gr3
      Fig. 3ROC curve of the predictive model elaborated for proctitis with the 95% confidence intervals depicted in dash lines.
      Fig. 4 reports the probability to suffer from proctitis calculated using the elaborated predictive model in function of the D98% of the low ano-rectum wall: to maintain an occurrence rate below to 27% a dose value below 25 Gy should be maintained-.
      Figure thumbnail gr4
      Fig. 4Histogram of the probability of proctitis occurrence calculated using the elaborated predictive model.

      Discussion

      This is a retrospective study whose aim was to find any correlation between dosimetric parameters and toxicity in patients with rectal cancer undergoing radiation treatment. Many studies in the literature have shown a significant association between rectal toxicity and different variables such us rectal volume exposed to high doses, RT techniques, contouring and DVH parameters.
      Bakkal et al. pointed out that modern RT techniques (IMRT, SIB) aim to reduce the doses of OARs providing safer doses for the treatment of rectal cancer. Buettner et al. showed that the fraction of the circumference of the rectal wall irradiated at high doses is specifically important. Krol et al. confirmed that less exposure of the rectal wall to intermediate or high doses of radiations, leads to fewer changes and complications [
      • Tucker S.L.
      • Dong L.
      • Cheung R.
      • Johnson J.
      • Mohan R.
      • Huang E.H.
      • et al.
      Comparison of rectal dose–wall histogram versus dose–volume histogram for modeling the incidence of late rectal bleeding after radiotherapy.
      ,

      Bakkal BH, Elmas O. Dosimetric comparison of organs at risk in 5 different radiotherapy plans in patients with preoperatively irradiated rectal cancer. Medicine (Baltimore) 2021; 100. Doi: 10.1097/MD.0000000000024266.

      ,
      • Buettner F.
      • Gulliford S.L.
      • Webb S.
      • Sydes M.R.
      • Dearnaley D.P.
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      Assessing correlations between the spatial distribution of the dose to the rectal wall and late rectal toxicity after prostate radiotherapy: an analysis of data from the MRC RT01 trial (ISRCTN 47772397).
      ,
      • Owens R.
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      • Padmanaban S.
      • Hawes E.
      • Jacobs C.
      • Weaver A.
      • et al.
      Intensity-Modulated Radiotherapy With a Simultaneous Integrated Boost in Rectal Cancer.
      ,
      • Krol R.
      • Hopman W.P.M.
      • Smeenk R.J.
      • Van Lin E.N.J.T.
      Increased rectal wall stiffness after prostate radiotherapy: relation with fecal urgency.
      ,
      • Peterson J.L.
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      • Diehl N.N.
      • Bernard J.R.
      • Tzou K.S.
      • et al.
      Image-guided intensity-modulated radiotherapy for prostate cancer: Dose constraints for the anterior rectal wall to minimize rectal toxicity.
      ,
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      • Akazawa M.
      • Scala M.
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      • et al.
      Proposed rectal dose constraints for patients undergoing definitive whole pelvic radiotherapy for clinically localized prostate cancer.
      ,
      • Alitto A.R.
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      • D'aviero A.
      • Piras A.
      • Frascino V.
      • et al.
      BIT-ART: Multicentric Comparison of HDR-brachytherapy, Intensity-modulated Radiotherapy and Tomotherapy for Advanced Radiotherapy in Prostate Cancer.
      ].
      In the era of personalized medicine, it is increasingly important to be able to predict toxicity and response to radiation treatment through radiomics and dosimetric parameters [
      • Cusumano D.
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      • Yu G.
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      • et al.
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      ,
      • Boldrini L.
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      • Lenkowicz J.
      • et al.
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      ,
      • Chiloiro G.
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      • Lenkowicz J.
      • Casà C.
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      • Boldrini L.
      • et al.
      Delta Radiomics Can Predict Distant Metastasis in Locally Advanced Rectal Cancer: The Challenge to Personalize the Cure.
      ,
      • Cusumano D.
      • Boldrini L.
      • Yadav P.
      • Yu G.
      • Musurunu B.
      • Chiloiro G.
      • et al.
      External Validation of Early Regression Index (ERITCP) as Predictor of Pathologic Complete Response in Rectal Cancer Using Magnetic Resonance-Guided Radiation Therapy.
      ,
      • Cusumano D.
      • Catucci F.
      • Romano A.
      • Boldrini L.
      • Piras A.
      • Broggi S.
      • et al.
      Evaluation of an Early Regression Index (ERITCP) as Predictor of Pathological Complete Response in Cervical Cancer: A Pilot-Study.
      ,
      • Catucci F.
      • Alitto A.R.
      • Masciocchi C.
      • Dinapoli N.
      • Gatta R.
      • Martino A.
      • et al.
      Predicting Radiotherapy Impact on Late Bladder Toxicity in Prostate Cancer Patients: An Observational Study.
      ].
      Rectal RT toxicity involves many early adverse effects that could interfere with the patient’s quality of life and daily activities.
      In the analysed cohort the most common adverse effects were diarrhea, dysuria and proctitis. In order to prevent these side effects, we looked for variables that were associated with them in an attempt to find any useful correlation.
      As Grade 1 toxicity has been shown to be uncertain and not correlated to treatment parameters, we performed an analysis considering as complications any events with Grade ≥ 2.
      A correlation was observed for Grade ≥ 2 toxicity with both clinical and technical parameters.
      Consistently to previously reported experiences [

      Bakkal BH, Elmas O. Dosimetric comparison of organs at risk in 5 different radiotherapy plans in patients with preoperatively irradiated rectal cancer. Medicine (Baltimore) 2021; 100. Doi: 10.1097/MD.0000000000024266.

      ], the type of technique was significantly correlated to the development of toxicity events (p-value of 0.03). Also for the D98% of the wall of the low ano-rectum, a statistical significance correlation was found (p-value of 0.043).
      Long-term results of the German CAO/ARO/AIO-94 phase III trial have shown that acute organ toxicity occurrence can be predicted based on basic patient characteristics such as gender in RT treatments [
      • Wolff H.A.
      • Conradi L.-C.
      • Beissbarth T.
      • Leha A.
      • Hohenberger W.
      • Merkel S.
      • et al.
      Gender affects acute organ toxicity during radiochemotherapy for rectal cancer: Long-term results of the German CAO/ARO/AIO-94 phase III trial.
      ,
      • Wolff H.A.
      • Conradi L.-C.
      • Schirmer M.
      • Beissbarth T.
      • Sprenger T.
      • Rave-Fränk M.
      • et al.
      Gender-Specific Acute Organ Toxicity during Intensified Preoperative Radiochemotherapy for Rectal Cancer.
      ]. Also in our cohort, Grade 2 toxicities resulted to be less frequent in men younger than 58 years, as the variable sex and age were significantly correlated to toxicity events (p-value of 0.03 and 0.045 respectively).
      Focusing on proctitis we found a correlation with the Dmean of the wall of the low ano-rectum (p-value of 0.03 and the p-adjust is 0.4) and a significant correlation with D98% of the low ano-rectum (p-value of 0.005 and the p-adjust is 0.08) and finally for D98% of the wall of the low ano-rectum we found a correlation with good statistical significance (p-value of 0.003 and a p-adjust of 0.06).
      This new model predicts that proctitis can be significantly reduced if the D98% of the wall of the low ano-rectum is < 38.5 Gy, allowing us to predict the risk of developing proctitis in relation to DVH and consequently to adjust it. This parameter may help radiation oncologists to reduce this side effect, especially if the tumor is located in the middle or upper rectum, but in general in all pelvic district cancers.
      In the case of tumors located in the ultra-low rectum, however, it may be more difficult to apply such a model because we may encounter target under-dosage. Therefore, to minimize the risk of this toxicity, this new parameter should simply be examined during the treatment planning validation. In our opinion it can be a valuable tool to help reducing acute toxicity from proctitis.
      Our study was a single-center retrospective series with a limited number of patients and therefore no definite conclusions can be drawn. It would be desirable to increase this type of research also in other centers to try in order to validate the model and find correlations between RT parameters and other side effects in patients undergoing RT for rectal cancer.

      Conclusions

      Although this study has several limitations such as being retrospective and the limited number of patients, the highly statistically significant value found is appealing and demands further research. Two dose constraints were elaborated: D98%<33.5 Gy for low ano rectum to prevent grade 2 acute toxicity and D98%<25 Gy for low ano-rectum wall to prevent proctitis (grade 1 or superior).

      Declaration of Competing Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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