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ORIGINAL ARTICLE
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The esophageal dose–volume parameters for predicting Grade I–II acute esophagitis correlated with weight loss and serum albumin decrease in lung cancer radiotherapy


 Department of Radiation Oncology, Suleyman Demirel University, Isparta, Turkey

Date of Submission14-Jun-2019
Date of Decision27-Aug-2019
Date of Acceptance26-Nov-2019
Date of Web Publication09-Oct-2020

Correspondence Address:
Zumrut Arda Kaymak Cerkesli,
Kaymak Cerkesli, Department of Radiation Oncology, Suleyman Demirel University, Isparta, 32200
Turkey
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_410_19

 > Abstract 


Introduction: Acute esophagitis (AE) is a commonly encountered side effect of curative thoracic radiotherapy (CTRT) for lung cancer patients. Nevertheless, its identification for widely used scoring systems depends on patients' statements. It is aimed to evaluate the correlation between the esophagus doses during CTRT and Grade 1–2 AE, weight change, and change in serum albumin (Alb) levels.
Subjects and Methods: The data collected from 124 lung cancer patients treated with ≥60 Gy CTRT were evaluated retrospectively. Weight and serum Alb level difference of each patient, throughout CTRT, were calculated. The percentage of the esophagus volume receiving ≥5 Gy (V5), V10, V35, V50, and V60; the absolute esophagus volume receiving ≥60 Gy (V60(cc)); the length of esophagus receiving ≥60 Gy (L60); the average esophagus dose (Dmean); and the maximum esophagus dose (Dmax) were the dose parameters calculated. The correlations were performed by Spearman's rank correlation coefficient.
Results: Grade 1 and Grade 2 AE were reported in 62 and 25 patients, respectively. All of the dose parameters were correlated with Grade 1–2 AE (P < 0.001) and weight loss (P < 0.001 for all, except Dmax P = 0.018). Decrease in serum Alb level was significantly correlated with all the parameters, but V5 and V10. Receiver operating characteristic curve analysis was performed for five parameters with the highest correlation coefficient (V35, V50, V60(%), V60(cc), and Dmean), and the cutoff values were 39.5%, 28.17%, 2.21%, 0.5cc, and 26.04 Gy, respectively.
Conclusions: The correlation of the dose parameters that might be effective on Grade 1–2 AE with the weight loss and Alb loss was investigated, and the cutoff values corresponding to the best sensitivity and specificity were identified.

Keywords: Acute esophagitis, dose parameter, lung cancer, radiotherapy



How to cite this URL:
Cerkesli ZA, Ozkan EE, Ozseven A. The esophageal dose–volume parameters for predicting Grade I–II acute esophagitis correlated with weight loss and serum albumin decrease in lung cancer radiotherapy. J Can Res Ther [Epub ahead of print] [cited 2020 Oct 27]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=297622




 > Introduction Top


Lung cancer has the highest incidence rate and is one of the main causes of cancer-related death worldwide and most patients present in advanced stage.[1] Curative thoracic radiotherapy (CTRT) is the standard treatment for limited staged small-cell lung cancer (SCLC) and Stage III non-small cell lung cancer (NSCLC).[2] In addition, CTRT is a treatment option for Stage I–II NSCLC patients who are medically inoperable or refused surgery.[3]

Esophagus is a critical organ of dose constraints in thoracic definitive radiotherapy (RT) for lung cancer, especially in patients with mediastinal lymph node involvement.[4],[5] Characteristic clinical features of acute esophagitis (AE) are substernal pain, odynophagia, and dysphagia, typically occurring 2–3 weeks after beginning of RT and relieving 2–3 weeks after completion of treatment.[6] 0%–26% of patients treated with CTRT may suffer from severe AE requiring IV therapy, hyperalimentation, or causing weight loss.[7] With concurrent chemoradiotherapy (CCRT) or hyperfractionation, severe AE rate increases to 15%–25%.[8],[9],[10]

The most commonly used scoring systems for AE are Radiation Therapy Oncology Group (RTOG)–Radiotherapy Acute Morbidity Criteria scale and National Cancer Institute–Common Toxicity Criteria scale.[11],[12] Grade 1 is defined as mild symptomatic and Grade 2 is defined as moderately symptomatic in both scoring systems. The definition of Grade 3 in RTOG scale includes 15% weight loss. Grade 1 and 2 AE do not include descriptive and objective statements as Grade 3. The grading of low or moderate AE is patient and physician dependent.

In dosimetric studies, the correlation of the esophageal dose parameters with especially ≥ Grade 2 or ≥ Grade 3 AE was investigated.[12] However, Grade 1–2 AE is more common in clinical practice, which also can lead to weight loss and serum albumin (Alb) decrease due to consequent malnutrition.[13],[14] Both weight loss and Alb decrease are defined as poor prognostic factors in lung cancer.[15] Therefore, one can predict that low-to-moderate AE seen during RT is a factor that can affect the prognosis of patients. This statement makes AE during RT a more important issue to be handled.

Vdose(the percentage of the esophagus volume receiving greater than a threshold dose), Dmean(the average dose of the esophagus); Dmax(the maximum dose of the esophagus), and Ldose(the length of the esophagus volume receiving greater than a threshold dose) are the most common dose parameters previously evaluated, which are considered to be associated with AE.[7]

The main purpose of this study is to take attention to Grade 1–2 AE as a complication of CTRT because of its frequency and clinical effect on treatment duration and quality of life. The relation of esophagus dose parameters not only with the grade of AE but also with weight changes and changes in serum Alb levels during CTRT was evaluated. It is aimed to determine the dose parameters objectively which are significantly predictive for low-to-moderate AE.


 > Subjects and Methods Top


Patients

Data were obtained retrospectively from the clinical records of 124 consecutive patients treated in our radiation oncology clinic between October 2011 and July 2018 who fulfilled the following criteria: (1) histologically confirmed limited-stage SCLC or nonoperable NSCLC, (2) underwent ≥ 60 Gy CTRT in 1.8–2.0 Gy daily fractions; (3) weight and AE grading recorded weekly during treatment; and (4) serum Alb levels available in the blood tests at the beginning and the end of the treatment. [Table 1] is representing patients' characteristics. Patients treated with palliative dose (>60 Gy) with metastatic disease and/or who had Grade 3–4 AE were not included in this study. Esophageal toxicity was scored using the RTOG–Radiotherapy Acute Morbidity Criteria scale [Table 2].
Table 1: Patient characteristics

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Table 2: Radiation Therapy Oncology Group grading for acute esophageal injury

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Radiotherapy and dosimetric parameters

A treatment planning computed tomography (CT) scan was performed by BrightSpeed Excel Select (General Electric Medical Systems) from the upper neck to the mid-abdomen with 2.5-mm slice thickness. Gross tumor volume was delineated as the primary tumor and involved mediastinal lymph nodes, via CT images fused with positron emission tomography-CT. Three-dimensional conformal radiotherapy (3D-CRT), intensity-modulated radiotherapy (IMRT), or field-in-field IMRT (FIF-IMRT) treatment plans were created using Eclipse treatment planning system on Varian DHX linear accelerator with anisotropic analytical algorithm dose calculation algorithm and 6–18 MV X-rays. A total of ≥ 60 Gy is used as a prescribed dose with 1.8–2.0 Gy daily fraction doses.

Delineation of esophagus was performed as the inferior border of the cricoid cartilage cranially to the gastroesophageal junction caudally and it was contoured on each axial slice of the planning CT images.

Dose–volume histogram was used to obtain dose–volumetric values for each patient. Esophageal dosimetric parameters calculated via treatment planning system for analysis were: Dmax and Dmean doses, the length of the esophagus that is receiving ≥ 60 Gy (L60), the percentage of the volume of the esophagus receiving ≥ 5 Gy (V5), V10, V35, V50, V60, and the absolute volume of the esophagus receiving ≥ 60 Gy (V60(cc)).

Serum Alb levels of the patients were obtained from the control blood tests at the beginning and end of the treatment and the differences between them were calculated. The differences between the recorded weights of the patients at the beginning and end of the treatment were also calculated.

Statistical analysis

All statistical analyses were performed using SPSS 21.0 software (IBM, Chicago, IL, USA). Spearman's rank correlation coefficient was used to analyze the correlation of the esophageal dosimetric parameters with the duration of Grade 1 or 2 AE, change in weight, and Alb levels. The cutoff values for the most significantly correlated parameters were found via receiver operating characteristic (ROC) curve analysis. The analysis was carried out considering P < 0.05 as statistically significant.

Ethical considerations

The study was approved by the Scientific Research Ethics Committee of Medical Faculty of University (protocol code, 46/05.02.2019). All procedures were performed in terms of the ethical standards of the institutional research committee in alliance with the 1964 Helsinki declaration and its later amendments. Informed consent was waived owing to the retrospective nature of the study.


 > Results Top


Of the 124 patients included in the study, 37 (29.8%) did not complain any symptom of esophagitis during the treatment. Grade 1 and 2 AE were recorded in 62 (50%) and 25 (20.2%) patients, respectively. The mean body mass index value of the patients at the beginning of the treatment was 24.3 ± 3.92. The median weight change during treatment was −1.45 kg (+4–[−7] kg). The median weight loss was 2.05% (0%–9.33%). The median change in the serum Alb level was −0.20 g/dl (+1.5–[−2.6] g/dl). The esophagus dose parameters are summarized in [Table 1] with median and range of values. All the parameters were significantly correlated with Grade 1–2 AE and weight loss (P < 0.001 for all, except Dmax and weight loss [P = 0.018]). [Table 3] shows the correlation coefficient values of correlation between dose parameters, decrease in serum Alb level, weight loss, and the severity of AE. The correlation between V5 and V10 volumes and decrease in Alb was not statistically significant. The five parameters found to have the highest correlation coefficient with Alb level decrease, weight loss, and the degree of AE were V35, V50, V60(%), V60(cc), and Dmean. To determine the cutoff values for these above-mentioned five dose parameters for Grade 1–2 AE, ROC curves were analyzed. The cutoff values to obtain highest sensitivity and specificity for V35, V50, V60, V60(cc), and Dmean were 39.5%, 28.17%, 2.21%, 0.50 cc, and 26.04 Gy, respectively. The values of the areas under the ROC curves, sensitivity, and specificity percentages are shown in [Table 4].
Table 3: Correlation between dosimetric parameters and weight loss, decrease in serum albumin level, and duration of Grade 1-2 esophagitis

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Table 4: Grade 1-2 acute esophagitis receiver operating characteristics analysis results of the best-correlated dose parameters

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 > Discussion Top


AE is one of the major causes of loss of amenity in lung cancer patients leading to interruptions of RT treatment. Interruption and consequent prolongation of the RT treatment is known to impair the treatment outcome and the synergistic effect of concurrent chemotherapy.[16] Severe AE is reported in 0%–26% of patients treated with CTRT because of lung cancer.[7] Therefore, it is of importance to evaluate the esophagus dose predictors for Grade 1–2 AE, which is rather more frequently encountered.

Our results were in accordance with some previously published reports in terms of AE rates (70.2% Grade 1 or higher and 20.2% Grade 2).[2],[15],[16],[17] Concurrent chemoradiotherapy (CCRT), advanced nodal stage, and hyperfractionation are reported to be related with severe AE in previous studies.[2],[3],[4],[5],[6],[7],[8],[9],[10],[14],[18],[19] IMRT provides more homogenous dose distribution than 3D-CRT and avoids hot spots. Hence, lesser severe AE rates may be predicted with IMRT. Nonetheless, there is conflict of data in the literature about the impact of the RT technique on AE. This issue has been investigated in a study showing Grade ≥ 3 AE in 28% of patients treated with IMRT where it was 8% in patients treated with 3D-CRT (P < 0.05).[20] On the contrary, Kwint et al. reported that AE risk was similar with IMRT or 3D-CRT.[21] Most of the patients were treated with FIF-IMRT technique (68.5%) in the current study, while patients planned with 3D-CRT (28.8%) or IMRT (2.7%) techniques were also included.

In addition to evaluation of the classic dosimetric parameters, the correlation between dose parameters, weight loss, and decrease in serum Alb along with the grade of AE was evaluated. These two clinical parameters could be considered as a reflection of malnutrition of the patients due to AE. ROC analysis was performed for the dose parameters displaying the best correlation with all three variables to obtain a more sensitive predictive criterion for AE than highest grade of esophagitis alone.

Our results revealed a statistically significant correlation between all parameters and duration of Grade 1–2 AE and weight loss during the treatment. V35, V50, V60(%), V60(cc), L60, Dmean, and Dmax were significantly correlated with the decrease in Alb levels, yet V5 and V10 did not have a significant correlation with the decrease in Alb. The predictive ability of V35, V50, V60(%), V60(cc), and Dmean to foresee the development of AE Grade 1–2 was tested by ROC analysis. The cutoff points for these five dose parameters with highest sensitivity and specificity to predict Grade 1 AE were calculated as 39.5%, 28.17%, 2.21%, 0.50 cc, and 26.04 Gy, respectively. In the study by Takeda et al.[15] with 34 lung cancer patients who underwent CTRT, esophagus dose parameters were correlated with Grade 1–2 AE. Takeda et al. observed a statistically significant correlation of Dmean, V10, V15, V20, V25, V30, V35, and V40 with Grade 1–2 AE and V35 was found to be the most significantly correlated parameter. In contrast with our results, they did not report any significant correlation between V50, V60, and AE. This contradiction may be attributed to the smaller sample size in that study.

Previously published data have indicated that volumes exposed ≥ 20–80 Gy or higher are significantly correlated with esophagitis,[7],[22] which is prominent for V30–V50.[2],[7],[15] Dmax, Dmean, and V60 were reported to be significantly associated with Grade 2–3 esophagitis in patients treated with 3D-CRT.[14],[18],[23] Maximum, mean dose, and V60 recommendations (Dmean≤ 34 Gy, max ≤ 105% of prescription dose, and V60 ≤ 17%) were adopted in the National Comprehensive Cancer Network guidelines.[24]

Our results showed that all of the esophagus dose parameters have an impact on low–moderate AE development in patients. In clinical practice, esophageal dose constraints are validated by V35, V60, and Dmean values in CTRT treatment plans. For the prediction of Grade 1–2 AE, it may be advisable to evaluate using further parameters with more sensitive dose limitations.

Higher the probability of esophageal toxicity is generally presumed with the longer length of esophagus segment included in the RT field; however, different opinions have been asserted regarding this issue. Ball et al.[25] divided 100 patients into three groups based on the length of the treatment field (<14.0 cm, 14.0–15.9 cm, and <16.0 cm), which is also expected to be related with the length of the esophagus in the field. The results of the study revealed no relationship between esophageal length in the field and the severity of esophagitis. Similarly, no correlation was found between grade of esophageal toxicity and the length of esophagus in the treatment field in the study by Choy et al.[6] The current trend is to encompass only the gross tumor with closer margins to ensure smaller and tighter fields[26] which we carried out for lung cancer patients enrolled in this study. It is also found a correlation between the length of esophagus receiving <60 Gy (median, 5.3 cm; range, 0–13.5 cm) and incidence of Grade 1–2 esophagitis, weight loss, and decrease in Alb level in the current study. However, the correlation coefficient of L60 was not as strong as the other first five best-correlated parameters.

Some points are required for further improvement in this study. First is the heterogeneous characteristics (stage and histopathology) and treatment modalities (RT technique, CCRT, or RT alone) of the entire group. As this is a single-center study, heterogeneous group of patients had to be analyzed to increase the study group. Second defect to notify is patient-based report of AE, which might cause undesirable deviation of the incidence and severity of esophagitis. Furthermore, the RTOG score is essentially variable. Unfortunately, current data lack sufficient objective and meticulous criteria to evaluate normal tissue complications.


 > Conclusions Top


Thoracic RT in locally advanced lung cancer is a treatment with many side effects. Therefore, patients should be informed about the efficacy and side effects of treatment in detail. Although esophageal dose parameters provide the recommended limits at the end of RT planning, patients can have Grade 1–2 AE. Grade 1–2 AE might cause malnutrition in patients leading to quality of life impairment and weight loss. It is important to evaluate the esophagus dose parameters to predict the risk of Grade 1 AE and to inform the patients about this issue. Suggestively, addition of clinical markers such as weight loss in definition of Grade 1–2 AE might help reduce the patient- and physician-based variability in the recording. As the studies investigating esophageal dose parameters which are predictive for mild–moderate AE during CTRT are quite limited in the literature, it could be stated that this paper is remarkable in this regard and can be a guiding one.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

 
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