{'fraction_non_alphanumeric': 0.02359040074557316, 'fraction_numerical': 0.01205731593662628, 'mean_word_length': 5.272926561929119, 'pattern_counts': {'":': 0, '<': 5, '<?xml version=': 0, '>': 4, 'https://': 0, 'lorem ipsum': 0, 'www.': 1, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Intratreatment Tumor Volume Change During Definitive Chemoradiotherapy is Predictive for Treatment Outcome of Patients with Esophageal Carcinoma

Background This study aimed to assess the predictive value of tumor volume changes of esophagus evaluated by serial computed tomography (CT) scans before, during, and after radical chemoradiotherapy (CRT) for treatment outcomes in patients with esophageal cancer (EC). Methods Fifty-three patients with histologically confirmed EC were included for analysis. Gross tumor volume of esophagus (GTVe) was manually contoured on the CT images before treatment, at a twentieth fraction of radiotherapy, at completion of CRT and three months after treatment. GTVe reduction ratio (RR) was calculated to reveal changes of tumor volume by time. The Kaplan–Meier method was used to estimate survival and for univariate analysis. The Cox regression model was performed for multivariate analysis. Results Predominant reduction of GTVe was observed during the first 20 fractions of radiotherapy. Age, pretreatment GTVe, GTVe three months after treatment and GTVe RR at twentieth fraction of radiotherapy were all significantly associated with overall survival (OS) in a univariate analysis. Gender was correlated with locoregional recurrence-free survival (LRRFS) in univariate analysis. Multivariate analysis showed that GTVe ≤20 cc, GTVe RR at twentieth fraction of radiotherapy ≥35% were positive predictive factors of OS and pretreatment GTVe ≤20 cc was prognostic for a favorable LRRFS. Conclusion Pretreatment tumor volume and intratreatment volume reduction ratio are reliable prognostic factors for esophageal cancer treated with definitive CRT.


Background
Esophageal cancer (EC) is one of the most common malignant tumors around the world. In China, it accounts for the fourth-leading overall cause of cancer deaths. 1 About three-quarters of patients with esophageal cancer are not suitable for curative surgery because of broad tumor invasion or patients' comorbidities. Concurrent chemoradiotherapy (CRT) is the standard care for nonsurgical candidates. However, long-term outcome for patients treated with CRT is poor, with five-year survival ranging from 20% to 40%. Therefore, it is of great value to classify patients as responders or nonresponders to CRT so that early intervention could be given to improve treatment outcomes. Pathological response was recognized as a reliable prognostic factor for patients treated with neoadjuvant CRT. [2][3][4] Nevertheless, in cases of definitive CRT, response evaluation is still a difficult issue as pathological response could not be accurately determined without complete resection specimen. 5 Though positron emission tomographycomputed tomography(PET-CT) is promising in predicting treatment response after CRT by functionally evaluating metabolic activity of tumor, [6][7][8] its application is limited in clinical practice as it is not readily available in primary health care institutes. Therefore, CT (computed tomography) is still the most commonly used imaging modality for response evaluation, especially in developing countries like China. Emerging evidence has proved that primary tumor volume was a prognostic factor for disease progression and survival in solid tumors, such as head and neck squamous cell carcinoma, lung cancer, and esophageal cancer. [9][10][11][12] A larger GTV is inversely related to survival. Chen et al reported that patients with pretreatment gross tumor volume of esophagus (GTVe) ≦20cc had better survival than those with GTVe >20cc. 13 Chen et al demonstrated similar results with a significant cut-off value of 39.41cm in 187 EC patients treated with definitive radiotherapy (IMRT). 14 Boggs et al indicated that primary GTV of esophagus is a more powerful predictor of patient outcomes than traditional TNM staging and GTV >85cc and GTV>46 cc were correlated with an increased risk of local failure and distant failure respectively. 15 Posttreatment GTVe is also found predictive for overall survival as those patients insensitive to CRT would have larger GTVe remaining after CRT. 16 Volumetric measurements of tumor shrinkage of esophagus were also found to be correlated with pathological outcome and locoregional recurrence (LRR) in patients undergoing neoadjuvant CRT. 17 However, the role of dynamic volume changes of esophageal tumor during and after definitive CRT in patients treated with radical CRT has not been studied before. A potential additional benefit of serial CT is the ability to view the ongoing response of the tumor to CRT, which allows physicians to adjust the treatment plan in time for those patients with modest response to treatment. The aim of this study is to investigate the relationship between volumetric comparison of esophageal cancer and prognosis.

Patients and Treatments
Our study is a correlative study with a single-arm, prospective phase II clinical trial "simultaneous modulated accelerated radiotherapy combined with chemotherapy for esophageal cancer" (clinical trial: NCT01670409) that commenced in Shantou University Medical College in August 2012. Major eligibility criteria included primary, pathologically confirmed esophageal squamous cell carcinoma without distant metastasis, unsuitable for surgery or patients who decline surgery. The study protocol has been previously published. 18 All patients were treated with definitive CRT. Simultaneous modulated accelerated radiation therapy (SMART) technique was applied for EC patients to deliver a higher dose of 66 Gy to gross tumor volume and a lower dose of 54 Gy to subclinical tumor volume in 30 fractions. All patients received two cycles of concurrent chemotherapy and two cycles of adjuvant chemotherapy.

Tumor Volume Assessment
All the patients underwent CT exams before treatment, at twentieth fraction of radiotherapy, at completion of treatment and three months after treatment using CT simulator (PHILIPS Brilliance Big Bore CT, Amsterdam, Netherlands). Patients were given an intravenous injection of contrast agent iopromide (75 mL) and simulated in a supine position with the entire thorax from lower neck to upper abdomen scanned. After scanning, axial images were reconstructed in 3-mm thick slices. Pretreatment GTVe was manually contoured on the pretreatment CT images by an experienced radiation oncologist utilizing information provided by barium radiography, CT scan with contrast, PET and endoscopic ultrasound. Pretreatment GTVe on CT images included area where eccentric or circumferential esophageal wall thickening was greater than 5 mm. Empty cavity of esophagus was eradicated from GTVe when contoured. The cranial and caudal borders of GTVe contoured during and after treatment were consistent with those of pretreatment GTVe and the entire esophagus in between was delineated ( Figure 1). GTVe on different CT images were all contoured by the same radiation oncologist to ensure consistency. The volume of GTVe was automatically measured by Eclipse 10.0 treatment planning system (Varian, CA, USA). GTVe reduction ratio (RR) compared with pretreatment GTVe was calculated to reveal changes of tumor volume by time, taking twentieth fraction of radiotherapy as example, RR=100×(pretreatment GTVe -GTVe at twenthieth fraction of radiotherapy)/pretreatment GTVe.
All patients were followed-up every three months after completion of CRT for the first two years then every six months for three years.

Statistical Analysis
The primary endpoint was overall survival (OS), which was calculated from the date of treatment to the date of allcause death or to the last day of follow-up. Secondary endpoint was locoregional recurrence free survival (LRRFS), defined as the interval between treatment and the earliest occurrence of disease progression resulting in LRR. We used repeated measures ANOVA (general linear model) to detect overall differences of GTVe at four separate time points (independent variable was time and level was four). Spearman bivariate analysis was used to reveal changes of GTVe by time of the whole group, with y variate referring to GTVe reduction ratio at three different time points of the whole cohort and X variate referring to time. Spearman coefficient (r) of every individual is calculated to show the trend of GTVe changes during and after treatment. We used the Kaplan-Meier method to estimate overall and LRRFS. Kaplan-Meier method was also applied for univariate analysis, with the Log rank test to ascertain significance. Prognostic factors with p<0.05 in univariate analysis, data of GTV and volume changes and other clinical characteristics which were reported closely related to prognosis were included in multivariate Cox proportional hazards models for further analysis. Considering the relatively small sample size, multivariate analysis was run twice for each time in which only five variates were included. And variates with p<0.05 were included for the final analysis. Significance was defined at a confidence level of p<0.05.

Results
The recruitment was completed in August 2015. Of all 87 patients, 53 (60.92%) patients underwent all four CT exams as designed and thus the CT scans of these patients were included for this analysis. Thirty-four patients were excluded because of missing tomographic exams as designed (20), disease progression (5), fail to follow adjuvant chemotherapy (3), esophageal fistula (2), death of esophageal hemorrhage (3) and death of noncancer related cause (1). Of all 53 patients, 41 were male, 12 were female, median age was 61 years old. Clinical characteristics were listed in Table 1 Figure 2). Tumor shrinkage was seen mostly in the first 20 fractions of radiotherapy.
GTVe and GTVe RR data at separate time points were listed in Table 2. Spearman coefficient (r) was 0.551 (p=0.00), meaning that tumor continued to shrink from commencement of treatment to three months after treatment.

Discussion
In clinical practice, imaging based evaluation of response is of great importance. Response evaluation criteria in solid tumors (RECIST 1.1) is the most widely adopted tool for response assessment of cancer therapeutics. 19 But it requires presence of measurable tumor lesions. As the RECIST guidelines caution, the primary lesion in the digestive tract is not a suitable measurable lesion in terms of reproducibility. In the case of EC, the longest diameter is difficult to define in repetitive measurements on CT images especially after radiotherapy. Maximal esophageal wall thickness had been utilized as substitute for longest diameter in a previous study by Li et al which showed that pre-and post-CRT maximal esophageal wall thicknesses were significantly correlated with pathological complete response, but no relationship between changes of esophageal wall thickness and survival was observed. 20 Our finding is consistent with most published data that a larger GTVe is closely related to a worse treatment outcome. In our study, patients with GTVe ≤22 cc had significantly better five-year OS and LRRFS (76.3% and 83.9%) compared to those with GTVe >22 cc (46.4% and 64.7%).
Previous studies have reported that tumor volume changes during treatment on the basis of evaluation by imaging modalities like CT and magnetic resonance imaging (MRI) was correlated with survival in rectal cancer and non-small-cell lung cancer. 12,21 The role of tumor volume changes in predicting treatment outcomes of esophageal cancer is still to be studied. Alfieri et al compared pre-and posttreatment tumor volumes and found that neither post-CRT tumor volume nor volume change were predictive of disease-free survival or overall survival though volumetric change seemed to be a moderate predictor of pathological T stage. 16 A similar result was achieved by another research study conducted by van Heijl et al, in which serial CT before and after two weeks of neoadjuvant CRT was performed in patients with esophageal carcinoma treated with neoadjuvant CRT. There was no statistical significance in tumor volume change between histopathological responders and nonresponders. Tumor volume changes after 14 days of neoadjuvant CRT measured by 3D-CT were not associated with histopathological tumor response. 22 However, Voncken et al analyzed relative tumor volume changes pretreatment and posttreatment in 56 EC patients. Their study revealed that relative tumor volume reduction following CRT was correlated with pCR, LRR, disease-free survival, and overall survival. The relative tumor reduction ≥20% was significantly correlated with a higher proportion of PCR and a longer LRR. 17 Nevertheless, the aforementioned studies were performed in the neoadjuvant CRT setting.
To the best of our knowledge, our study was the first one to use serial CT scans for response evaluation for EC patients undergoing definitive CRT. There is no standard guideline for posttreatment tumor contouring. Regarding peritumoral edema, radiation-related fibrosis and inflammation after radiotherapy, esophageal wall thickness may not be an accurate reference. To better compare tumor volume changes with baseline data, we contoured GTVe during and after treatment between cranial and caudal borders of GTVe consistent with those on pretreatment CT images. This method could improve accuracy and reproducibility in measuring tumor volumes among different observers. It was also proved to be a reliable reflection of tumor burden. As seen on Figure 2, a linear reduction of GTVe in the first four weeks of CRT was observed in most patients. The five-year OS rates were 47.7% in patients with GTVe RR at twentieth fraction of radiotherapy <35% vs 73.0% in those with GTVe RR ≥35%. This result indicated that gross tumor volume reduction ratio is a promising parameter to differentiate responders from nonresponders to definitive CRT. The sensitivity to CRT may be predicted as early as at twentieth fraction of radiotherapy. Responders who would benefit most from CRT should continue planned therapy. But for nonresponders, early intervention should be taken to improve treatment outcomes, like surgery or changing adjuvant chemotherapy regimen. Since the publication of the CROSS study in 2012, neoadjuvant CRT followed by esophagectomy has become standard care of resectable locally advanced EC. 23 Compared with the surgery alone group, patients who received multimodality therapy had significantly longer survival. Though many patients who received definitive CRT are not candidates for curative esophagectomy because of broad tumor invasion, tumor shrinkage after CRT may enable surgery and allow for adequate clean margins. Furthermore, the accumulative radiation dose of 20 fractions is close to the total dose of neoadjuvant CRT as in the CROSS study (41.4 Gy in 23 fractions).

DovePress
Thus, we suggest a CT exam at twentieth fraction of radiotherapy for tumor response assessment for all patients who underwent definitive CRT. If patients have GTVe RR <35%, reevaluating the feasibility of a curative or salvage surgery would be indicated.
There were some limitations of our study. Firstly, volume changes of lymph nodes were not involved in prognostic analysis because of a small percentage of patients with measurable lymph nodes in our study and low predicting rate of pathological lymph nodes with CT scanning alone. 20,24 Another limitation is the relatively small number of study subjects as only 53 eligible patients were included for analysis. In our study, we took the median value of GTVe reduction ratios at twentieth fraction of radiotherapy fraction (35%) of the whole cohort as the cut-off value. Further research with bigger sample sizes are needed to determine an optimal cut-off value. Despite the aforementioned limitations, our study proved that serial CT played an important role in response evaluation in EC patients undergoing definitive CRT. For health care institutes not equipped with PET-CT, tumor volume reduction ratio is a reliable parameter to recognize responders from nonresponders and further to guide clinical decision-making.

Data Sharing Statement
Derived data supporting the findings of this study are available from the corresponding author Chuangzhen Chen on request.

Ethics Approval and Informed Consent
Ethical approval for patient recruitment and data collection in our trial was approved by the Clinical Research Ethics Review Committee of Cancer Hospital of Shantou University Medical College (Approval No. 005). All patients in the trial provided written informed consent, and this trial was conducted in accordance with the Declaration of Helsinki.

Publish your work in this journal
Cancer Management and Research is an international, peer-reviewed open access journal focusing on cancer research and the optimal use of preventative and integrated treatment interventions to achieve improved outcomes, enhanced survival and quality of life for the cancer patient.
The manuscript management system is completely online and includes a very quick and fair peer-review system, which is all easy to use. Visit http://www.dovepress.com/testimonials.php to read real quotes from published authors.