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ORIGINAL ARTICLE
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Evaluating the relationship between dosimetric parameters and esophagitis in patients who experienced radiotherapy in the cervicothoracic region


1 Department of Radiotherapy Oncology, Shohada Tajrish Hospital, School of Medicine, Shahid Beheshti University of Medical Science, Tehran, Iran
2 Department of Radiology Technology, School of Allied Medical Sciences, Shahid Beheshti University of Medical Science, Tehran, Iran
3 Department of Radiotherapy Oncology, Emam Hosein Hospital, School of Medicine, Shahid Beheshti University of Medical Science, Tehran, Iran
4 Department of Biostatics, Proteomics Research Center, School of Allied Medical Sciences, Shahid Beheshti University of Medical Science, Tehran, Iran

Date of Submission27-Jan-2020
Date of Decision15-Jul-2020
Date of Acceptance12-Aug-2020
Date of Web Publication13-Jul-2021

Correspondence Address:
Mohsen Bakhshandeh,
Department of Radiology Technology, School of Allied Medical Sciences, Shahid Beheshti University of Medical Science, Tehran
Iran
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_91_20

 > Abstract 


Purpose: Prescribing radiotherapy or concurrent chemoradiation for cervicothoracic cancers inevitably leads to esophagitis. The purpose of the current study was to evaluate the correlation between the dose–volume parameters and the esophagitis in patients who received radiotherapy in the cervicothoracic region.
Materials and Methods: Forty cancerous patients whose radiotherapy fields were in the cervicothoracic region have been rolled. The correlation between the dosimetric and clinical factors with esophagitis was analyzed through binary logistic regression model and Pearson correlation tests and was quantified with receiver operating characteristic curve.
Results: The patients participating in the study were selected from breast (6 cases), lymphoma (7 cases), and head-neck (27 cases) patients with prescription doses of 36–72 Gy. Increasing esophagus mean dose resulted in an increase of acute esophagitis significantly (P = 0.05). Furthermore, by one-gray increase in the esophagus median dose, the possibility of esophagitis increased by 9.3% (P = 0.02). To prevent acute esophagitis (Grade ≥2), D50 should be kept below 7 Gy. To limit acute esophagitis, V40 should be kept below 19% (P = 0.04).
Conclusions: Based on the correlation analysis of the current study, concurrent chemoradiotherapy, DMean, D50, D80, and V40 are known as reliable predictive dosimetric parameters of acute esophagitis incidence in patients who experienced radiotherapy in the cervicothoracic region.

Keywords: Cardiothoracic region radiotherapy, esophagitis, esophagus dose–volume histogram parameters



How to cite this URL:
Siavashpour Z, Rabiee N, Bakhshandeh M, Anvari A, Zayeri F. Evaluating the relationship between dosimetric parameters and esophagitis in patients who experienced radiotherapy in the cervicothoracic region. J Can Res Ther [Epub ahead of print] [cited 2021 Jul 29]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=321274




 > Introduction Top


Radiation therapy uses high-energy radiation to shrink the tumor and destroy cancer cells, which can also cause acute and chronic complications in the surrounding normal tissues. Prescribing radiotherapy or concurrent chemoradiotherapy for cervicothoracic cancer inevitably leads to esophagitis, which emerges as responses to esophageal mucosa irradiation.[1],[2]

The esophagus is more susceptible to radiotherapy sequela due to the continuous replacement of mucosal cells. Mucosal inflammation and epithelium destruction can increase obstruction and ulceration.[3] Esophagitis is divided into two acute and chronic categories.[4] In general, acute complications occur <3 months after the end of radiotherapy. However, chronic esophagitis usually begins 2–3 weeks after initiation of radiotherapy and lasts up to 4 weeks after its final fraction.[5],[6] Signs of acute esophagitis include dysphagia, nausea, anorexia, painful swallowing, and heartburn. If these symptoms get worse, they may lead to dehydration, malnutrition, and respiratory problems and weight loss.[7],[8] Chronic esophagitis lasts for more than 3 months, an average of 6 months, or in some cases even 1 year or more. Acute one can be diagnosed clinically without any special examination. Endoscopy is useful for the diagnosis and treatment of chronic esophagitis as well as to differentiate esophagitis from the infection.[7] The multiplication of invasive radiotherapy techniques (such as hyper/hypofractionation radiotherapy and simultaneous boost), adding concurrent chemotherapy to treatment indications, and the patients' several clinical factors (e.g., previous dysphasia, nodal stage elevation) increase the rate of acute esophagitis.[5] Concurrent chemotherapy can significantly cause acute esophagitis of Grade 3 or worse.[9] The patients may need to be hospitalized because of acute esophagitis due to the simultaneous chemotherapy so the discontinuation of radiotherapy reduces the local tumor control.[10] These complications significantly affect the quality of life and have a negative impact on long-term survival.[11]

Therefore, risk factor identification of acute esophagitis is very important for optimizing the whole radiotherapy/chemotherapy dose adjustment procedure and reducing the treatment toxicity. Acute esophagitis has been characterized in terms of clinical predictor and dosimetry factors.[12] Dose–volume histogram (DVH) parameters are often used to analyze and predict the risk of acute esophagitis.[13] Among published studies, there are still some controversies on choosing general predictive DVH parameters that have the greatest effect on the risk of acute esophagitis for the patients whose radiotherapy fields cross through the cervicothoracic region.[14] Currently, it is not possible to identify the best threshold parameter of esophagitis due to a wide range of parameters which are significantly associated with mild (Grades 0–1) to severe acute (grades ≥2) esophagitis.[15] Acute esophagitis optimal dosimetric predictors likely vary for different clinical conditions. Therefore, more studies, based on the various radiotherapy and chemotherapy combinations, are required.

On the other hand, there are some useful dose constraints suggested by the Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC), but these recommendations consider neither the irradiation of each esophagus segment (i.e., cervical, thoracic, or abdominal) nor the length of the irradiated esophagus.

Based on the several recent radiobiological studies, it is obvious that “genetic and lifestyle factors” can play important roles in the radiation-associated disease susceptibility of different societies.[12] However, there are some effective markers' scarcities in detecting acute esophagitis during radiotherapy of the thoracic region. Accordingly, due to the increase in the various chemoradiotherapy protocols, dose–response assessments and finding more reliable predictive factors for complex acute esophagitis, therapeutic efficacy, and side effect analysis may need to be done in different societies. Statistical analysis of esophagitis requires making use of multivariate models.

In the present study, the dependency of the acute esophagitis on the dose–volume parameters of patients who underwent cervicothoracic radiotherapy was investigated in order to determine the most predictive factors of this sequela occurrence in patients belonging to the geographical area under study who probably have more similar genetic features. In addition, dependency of the mentioned side effects on the position and length of the irradiated esophagus was also studied. Choosing an individualized and effective treatment from the proposed standard options can be more reasonable by having insight into the patients' specific factors for treatment evaluation regarding their society/genetics.


 > Materials and Methods Top


The present study was cross-sectional research that was performed for patients who had cancer and have been prescribed to get radiotherapy in the cervicothoracic region at the department of chemo/radiotherapy, Emam Hosein hospital, Tehran, Iran. Inclusion and exclusion criteria are presented in [Table 1]. Patients' information included age, sex, type of cancer, and history of chemotherapy and medical history. Not any other confounding factors such as smoking status were considered due to the obtained nonsignificant difference between the prediction ability of radiobiological models for high-grade radiation esophagitis with/without considering clinical factors.[16],[17]
Table 1: Inclusion and exclusion criteria in case selection

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The time frame of recruiting patients was designed based on the predefined timeline of the current study which was 12 months and also the time needed for patients to be followed up in 3 months after finishing their radiotherapy. Therefore, 9 months was considered as deadline to add any new patient who met the inclusion criteria to the study. Ethical approval for this study was obtained from the ethics committee of Shahid Beheshti University of Medical Science.

For all patients, the same computed tomography (CT) simulation for radiotherapy (Toshiba®, Aquilion 16) was used. Treatment planning system was Isogray® (DOSIsoft SA). Chronic esophagitis was not followed. Grade 0–1 of RTOG 9410 mild acute esophagitis was named “mild esophagitis” and Grade ≥2 of RTOG 9410 severe acute esophagitis was named “acute esophagitis” through the following steps for convenience.[9],[11]

The total length of the esophagus from the cricoid cartilage to the connective area of the stomach was segmented in CT images based on the RTOG contouring guidelines.[13] All of the esophagus contouring was done by an expert radiation oncologist to eliminate the interobserver delineation errors.[14] Mean dose (Dmean) <34 Gy is known as the recommended dose constraint based on the QUANTEC analysis.[15] Furthermore, there are some other DVH parameters such as the volume of the esophagus receiving more than 35 Gy, 50 Gy, and 60 Gy (i.e., V35, V50, and V60) which were assessed and recorded. All of these DVH parameters were correlated with Grade 2–3 of esophagitis and even stricture and perforation.[15],[18]

The other DVH recorded data were Vxs (i.e., volume of the esophagus receiving ≥ x Gy) which included V5, V10, V15, V20, V25, V30, V35, V40, V45, V50, V55, V60, V65, and V70. Furthermore, the minimum dose to the different volume percentages of the esophagus (Dx) included D10, D20, D30, D40, D50, D60, D70, and D80 that were calculated.

The prescribed dose for each patient was determined by an oncologist according to the type of cancer, stage, and other clinical considerations, but the dose for each radiotherapy fraction was 1.8–2 Gy as conventional treatment. Esophagitis symptom evaluation was done before radiotherapy, at the onset of radiotherapy, weekly during radiotherapy, 1 month, and then 3 months after the end of radiotherapy. Esophagitis diagnosis and grading were done by the oncologist based on the RTOG and Common Terminology Criteria for Adverse Events version 4.03 grading for acute esophagitis[19],[20] and then recorded in the questionnaire by the oncologist's examinations and final decision. The correlation between the DVH parameters and different acute esophagitis grades were analyzed by the IBM SPSS® software platform (version 23, IBM Company, Chicago, USA). The irradiated esophagus volume (IEV) and the esophagus length which received at least 20, 30, 40, 45, 50, and 60 Gy were also recorded and evaluated. IEV was defined as V5 (IEV = V5) in the analysis step. Binary logistic regression model was used to extract the relationship between acute esophagitis as the dependent variable and the dosimetric/clinical parameters as the independent variables individually. Using appropriate regression models resulted in 95% confidence intervals for the occurrence probability of this complication's different grades. Odds ratio (OR) in binary logistic regression model is a key constant which represents the success probability of some events. We utilized this constant to demonstrate the esophagitis occurrence probability for each dosimetric studied parameter. Pearson correlation coefficient was used to find the interrelationship between the independent variables and the esophagitis.[21] Again, the confidence interval of the correlation coefficient was known to be 95%. The capability of each DVH parameter and other covariates to find the more reliable prediction of different esophagitis grades, was quantified with receiver operating characteristic (ROC) curve and its area under the curve (AUC), nonparametrically.[1]


 > Results Top


Patients were excluded from the study when they revealed to be metastatic during the primary treatment, acute treatment side effects cause their inconvenience, or any treatment gap/delay was prescribed for them between the RT courses. Finally, following inclusion criteria and study timeline, 40 patients were considered and followed up. However, the sample size was in accord with some previous studies.[22],[23] The individuals were selected from among breast (6 cases), lymphoma (7 cases), and head-neck cases (27 cases) with a mean age of 56.62 ± 11.78 year. The range of prescription doses was 36–72 Gy. Furthermore, 42.5 and 57.5% of the patients were male and female, respectively. Frequency of mild esophagitis (i.e., Grades 0 and 1) was 27 patients (67.5%) and acute esophagitis (i.e., Grade 2 and upper) was 13 patients (32.5%). The percentage of patients with Grades 0, 1, 2, and 3 of esophagitis was 35%, 32.5%, 22.5%, and 10%, respectively. No case was diagnosed with Grades 4 and 5. For most of the patients, esophagitis symptoms commenced after 2 weeks of radiotherapy. Acute esophagitis probability rose when the patients' age increased (7%) and it was one and a half times more in men than the women. However, both findings were not statistically significant (P > 0.05).

Sixty percent of considered cases were delivered concurrently chemotherapy with radiation therapy. Chemotherapy increased the probability of acute esophagitis significantly (P = 0.03). However, there was no significant relationship between chemotherapy and mild esophagitis.

No significant relationship was found between the radiotherapy number of fields and different degrees of esophagitis. Based on the current study results there is no correlation between esophagitis complication and irradiated esophageal parts (i.e., lower, middle, or upper).

The esophagus Dmean was 22.4 ± 17.8 Gy and 27.7 ± 15.5 Gy for patients with esophagitis Grade 2 and 3, respectively. A significant increase was presented in the acute esophagitis probability as the esophagus Dmean increased (P = 0.05). Furthermore, our results demonstrated 9.3% growth in the acute esophagitis probability by one-gray increase of the esophagus median dose (DMedian) (P = 0.02).

[Table 2] represents the results of logistic regression model for the relationship between acute esophagitis and the considered DVH parameters.
Table 2: Relationship between the esophagitis and the considered dose-volume histogram parameters

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There were significant and positive correlations between mean and median esophagus dose with acute esophagitis. Both P values were 0.01, and their correlation coefficients (r) were 0.39 and 0.43, respectively.

Another factor assessed was the volume of the irradiated esophagus and its effect on the considered complications. One cc increasing of the IEV resulted in a 5.7% growth in the probability of acute esophagitis (P = 0.02). Moreover, [Table 3] represents the relationship between the esophagus length which was irradiated by different mentioned doses and acute esophagitis. No significant relationship was obtained between these lengths and mild complication.
Table 3: Relationship between the irradiated esophagus length and esophagitis

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ROC analysis results for assessing the prediction ability of dosimetric parameters under study are presented in [Table 4].
Table 4: Receiver operating characteristic analysis of dose-volume histograms prediction ability for esophagitis

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 > Discussion Top


Nowadays, the demand of radiotherapy is about 48% for the cancerous patients, and the radiotherapy filed will be around the cervicothoracic region (i.e., breast, lymphoma, head, and neck) for 52% of them.[24] The cancer incidence and mortality rate such as breast and gastric are increasing in Iran.[25] Treatment planning and dose delivery conformity have increased thanks to new technologies such as intensity-modulated radiation therapy and volumetric modulated arc therapy. However, acute esophagitis is still known as a significant complication during and after radiotherapy with/without concurrent chemotherapy for the patients whose radiotherapy fields pass through the cervical and thoracic region.[26]

A significant esophageal contouring interobserver uncertainty was reported in RTOG 0617; therefore, we asked an expert oncologist to contour the esophagus of all the considered cases in blind to the patients' history.[27]

The number of patients with mild acute esophagitis (i.e., Grades 0 and 1) was higher than the severe acute esophagitis (i.e., Grades 2 and 3) in this study. Frequency of mild esophagitis (i.e., Grades 0 and 1) was 27 patients (67.5%) and acute esophagitis (i.e., Grade 2 and upper) was 13 patients (32.5%). This finding was consistent with Socinski et al. study which demonstrated the acute esophagitis occurrence in 50% of the patients who received 60–65 Gy total dose. Nevertheless, only 1%–5% of the patients who were exposed to 45–55 Gy experienced mild esophagitis.[28] About 70% of our neck and thorax cases' prescription dose was equal or less than 60 Gy, so the complications grade were in accordance with the previous published results. Furthermore, Zhang et al. found that 51 cases of 70 patients got Grade 2–3 esophagitis.[29] However, it is useful to mention that the presence of mild hemorrhagic esophagitis symptoms and the early diagnosis of the complication prevent its progression to severe levels.

Because the average patient's age (56.6 ± 11.8 years) led to a 7% increase in OR for Grade 2–3 esophagitis with the multivariate analysis of the current study, it is important to evaluate this radiation side effect, especially in older patients. However, this difference was not significant (P = 0.08) for this population which was in agreement with the previous research studies.[17],[30] Payal et al. even showed an esophagitis lower incidence with increasing lung cancer patient's age and also elderly patients can tolerate thoracic radiotherapy.[17] In line with the current study results, several studies indicated a significant increase in the acute esophagitis risk with concurrent chemotherapy.[1],[28],[31],[32]

QUANTEC, RTOG 0617, and Emami normal tissue complication probability models and DVHs assessment results were used in the current study for treatment planning approval.[15],[18],[33],[34] Therefore, it was attempted to keep the DMean of the esophagus ≤34 Gy. However, our patients' average DMean with Grade 2 and 3 acute esophagitis was about 12 Gy and 6 Gy less than the suggested one, respectively. Even by considering the mentioned protocols, we would expect more than 30% of the complication rate. Like our findings, Paximadis et al. encountered Grades 2 and 3 esophagitis in 61% of their cases which esophagus DMean was ≤23 Gy.[1] Furthermore, DMedian is supposed as a good indicator and surrogate for acute esophagitis. As shown in [Table 2], by increasing Dx, the probability of acute esophagitis was increased significantly. Among these kinds of DVH parameters, D80 was the most reliable factor in occurrence prediction of Grade 2 and 3 esophagitis which one-gray increase in it resulted in 82% growth in the esophagitis incidence probability (P = 0.03). The logistic regression indicated that almost all of the Vx independent parameters (except V70) had a direct and significant relationship with acute esophagitis. As an example, when the esophagus volume increased 1%, received at least 5 Gy, the esophagitis probability would increase 6%. In Zhang et al. study, with logistic regression analysis of DVH parameters, the only parameter that had a significant relationship with esophagitis was V40. They chose 23% of esophagus volume as a cutoff point during their analysis and concluded that if the V40 was ≤23%, the occurrence risk of Grade 2 esophagitis would be 33%, and if V40 was >23%, it would increase to 89%.[29] In the current study, 19% of esophagus volume was considered as the optimized cutoff point and 73.2% of the concluded cases were classified correctly in this point. Our results are in accordance with Pan et al. data. They also figure out that V40 is a reliable predictive parameter for acute esophagitis.[35]

We did not find any significant correlation between the irradiated esophageal parts and esophagitis. Contrary to the present study, Pan et al. and Huang et al. reported that the upper part of the esophagus was more sensitive to radiation.[35],[36] They believed that the different distributions of the sensory axons and different physiological structures of different esophagus parts were the reasons of this sensitivity.[36] However, their results are also contrary to Jelvehgaran et al. recent research.[37] Their study on the radiosensitivity of mice esophagus proved that the distal portion of the esophagus was more sensitive to radiation. The gastroesophageal refluxes were the reason of this event according to their research.[37] Because of the excessive lung cancer researches, we did not pay attention to it. Moreover, the upper and middle parts of the esophagus received a dose in this research. Besides, any further studies are required to illustrate different portions of esophagus sensitivities according to the more reliable diagnostic protocols which are independent of the interphysician bias and the larger sample size.[1]

The higher the AUC, the more predictive the DVHs and other independent variables for acute esophagitis. Regarding the AUC definition and suggestion of previous researchers, the ROC test results were interpreted as follows: AUC < 0.70, low prediction reliability; AUC in the range of 0.70–0.90, moderate prediction reliability; and AUC ≥0.90, high prediction reliability.[38],[39] The AUS results [Table 4] demonstrated that D50, D70, DMedian, V25, V35, and V40 can be reliable predictor for acute esophagitis. The most predictive DVH parameters for acute esophagitis were the average dose to the whole organ which could be justified by the serial feature of the esophagus. Cutoff points reduction from V5 to V65 and also from D10 to D80 in [Table 4] means that the same complication will be expected if a small volume of the esophagus was exposed to high doses or a large volume of the esophagus to small doses. V70 could be recognized as an outlier based on our sample size and prescription doses. As an example, considering 7 Gy as the D50 cutoff point, 69.2% of the acute esophagitis cases and 67.3% of the mild esophagitis cases were classified correctly according to [Table 4] results. At this cutoff point, approximately 71.5% of the total patients were correctly classified. As a result, to prevent acute esophagitis (Grade ≥2), D50 should be kept below 7 Gy.

Finally, the presented study proved the significant dependency of esophagitis risk on the esophagus Dmean, indicating that the radiotherapy Dmean growing significantly caused an increase in the risk of acute esophagitis. Furthermore, it illustrated if the minimum volume of the esophagus with different doses increased, the risk of esophagitis significantly would increment. V40 had a direct and significant relationship with acute esophagitis and its optimal cutoff value was about 19%. Another reliable DVH parameter for prediction of the risk of acute esophagitis was the minimum dose to at least 80% of esophagus volume. A direct correlation was obtained between concurrent chemotherapy and acute esophagitis. A small sample size can be considered as one of the study's limitations. Therefore, further randomized multicenter study with more patients who belong to the same geographical area but with almost similar genetic characteristics is necessary to confirm the physical and biological factors for prediction of acute esophagitis.[31],[32]


 > Conclusion Top


From this prospective local study, we get some reliable dosimetric factors which had a significant correlation with acute esophagitis in patients who underwent thoracic radiotherapy. Concurrent chemotherapy, DMean, D50, D80, and V40 are these reliable predictors. In conclusion, paying attention to these dosimetric parameters entails better expectation of this low-risk complication occurrence. Another limitation of this study was the absence of different genetic patients' data comparison of esophagus radiosensitivity with optimized dosimetric and biological predictor selection proposed for different genetics by utilizing a similar treatment protocol and similar side effect diagnostic protocols.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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