Abstract
Background: For patients with esophageal squamous cell carcinoma (ESCC) with oligo-recurrence (OR) after previous curative radiotherapy and not eligible for radical resection, the role of radical re-irradiation was not clear. Therefore, we aimed to investigate the outcome and prognostic factors of such patients. Patients and Methods: We identified patients with OR of ESCC after previous curative radiotherapy and were treated with radical re-irradiation within 2012-2018 via an in-house prospectively established database. The characteristics of patients, disease, treatment, and outcome were retrospectively obtained via chart review. The first day of re-irradiation was defined as the index date. Overall survival was calculated via the Kaplan–Meier method. Log-rank test was used for univariate analysis and Cox regression method was used for multivariable analysis. Results: We identified thirty patients for analyses. After a median follow-up of 9 (range=2-76) months, the 5-year overall survival rate was 21%. Four patients with possible radiotherapy-related complication in need of inpatient care were identified. Gross tumor volume was the only significant prognostic factor in both univariate and multivariable analyses. Conclusion: We found that radical definitive re-irradiation may lead to one-fifth long-term survivors of patients with OR after previous curative radiotherapy for ESCC, and the gross tumor volume was the only significant prognostic factor for these patients. Randomized controlled trials should be considered to compare radical re-irradiation with the current standard of care (systemic therapy) for this population.
Esophageal cancer is a common cancer worldwide (1). Common histology differs for eastern (squamous cell carcinoma) and western (adenocarcinoma) populations (1, 2), and radiotherapy is a common treatment modalities (3-5). The prognosis of esophageal cancer is poor, and the recurrence rate high (1). At the time of recurrence, treatment options are often limited and palliative (1, 5). For patients who have persistent/recurrent esophageal squamous cell carcinoma (ESCC) after previous curative radiotherapy which is not amenable to radical resection, systemic therapy or best supportive care are the current standard of care (3).
However, for those with oligo-recurrence (OR), the optimal treatment is less clear. Radical local treatment was advocated for oligo-metastatic disease in several randomized controlled trials (RCT) (6-8). For ESCC, surgery is the preferred modality as reported in a systemic review published in 2016 and suggested in the 2019 Japanese guideline (5, 9). On the other hand, the role of radical re-irradiation is usually less certain (10, 11). In the four studies included in the above-mentioned systemic review (12-15), three reported no 2-year survivors for the non-surgical group, whereas the 3-year overall survival rate 12% was reported in the fourth study (14). However, the case number in the non-surgery group was small in all four studies in this systematic review, ranging from 13-36 patients.
Patient characteristics (n=30, all male).
Kaplan–Meier overall survival curve with 95% confidence interval.
Due to these drawbacks in the literature, we aimed to investigate the outcome and prognostic factors of patients with OR of ESCC after previous radiation and treated with radical re-irradiation via retrospective review of patients treated at our Institute.
Patients and Methods
Study population. We identified patients with OR of ESCC after previous curative radiotherapy and who were treated with radical re-irradiation within 2012-2018 via an in-house prospectively established database. Our inclusion criteria included: (i) History of histological confirmation of ESCC; (ii) OR [by restaging positron-emission tomography (PET)] after previous curative concurrent chemoradiotherapy (CCRT); (iii) unsuitable for surgery and treated with radical re-irradiation. Radical re-irradiation was defined as at least 45 Gy at 1.8-2 Gy/fraction (90% of the recommended minimal 50 Gy in the treatment guideline) (3). The characteristics of patients, disease status, treatment, and outcome were retrospectively obtained via chart review and confirmed with the referring physicians. This study was approved by the Ethics Committee of our institute [CMUH106-REC3-119 (CR2)].
Re-irradiation. Patients were treated with 6- or 10-MV linear accelerators. Generally, a thermoplastic cast was used for immobilization then simulations with computed tomography (CT) were carried out in the treatment position. The gross target volume (GTV) was defined as the region of OR in the simulation CT image with the information from the restaging PET/endoscopic examination or diagnostic CT. At least 5 mm margin with editing was added to form the clinical target volume for most patients. We then added a 6-10 mm margin for the planning target volume to be used in intensity-modulated radiotherapy (IMRT) planning. Dose distribution and doses to the organs at risk in the summed plan via rigid fusion with previous radiation were evaluated whenever possible. Image-guided radiotherapy was used in the setup due to patient preference (in need of out-of-pocket payment).
Running log-rank test for different tumor volume cut-off points.
Statistical analysis. The first day of re-irradiation was defined as the index date. Overall survival was calculated from the index date to the last date of contact or death via the Kaplan–Meier method. Log-rank test was used for univariate analysis and Cox regression method was used for multivariable analyses to adjust for covariables before or at the time of re-irradiation. The inclusion and classification of these covariables were based on our clinical experience. Statistical analysis was performed using software R package “survival”.
Results
Study population and treatment. We identified 30 eligible patients (all male). The median age at re-irradiation was 59 (range=45-82) years. Most patients had locally advanced [clinical stage II-III by American Joint Committee on Cancer (AJCC) seventh edition staging (16)] at diagnosis and were treated with definitive CCRT with median 50 Gy radiotherapy dose (Table I). At the time of re-irradiation, after a median interval of 11 months from the previous radiotherapy, most patients had good performance status [Eastern Cooperative Oncology Group performance status (ECOG PS) 1] and had pathological proof of OR located in the chest with median re-irradiation dose of 50.4 Gy, mostly concurrently with chemotherapy.
Subsequent treatment and clinical outcomes. Nineteen patients received subsequent systemic therapy after re-irradiation but only four patients received additional radical local treatment during follow-up. At the time of analysis, after a median follow-up of 9 (range=2-76) months, 23 had died. The median (range) follow-up for the survivors was 51 (22-76) months. The 5-year overall survival rate was 21% as estimated via the Kaplan–Meier method (Figure 1). Twenty-two patients had radiologic or symptomatic improvement after re-irradiation recorded in their medical charts. Four patients without disease progression had possible radiotherapy-related complications in need of inpatient care. Among these four patients, one developed esophageal stricture and was treated with incision but was complicated by mediastinitis, which improved after in-patient supportive care. Three patients developed fistula which led to death in two of them.
Univariate analysis.
Multivariable analyses.
Prognostic factors. In univariate analysis (Table II), none of the included covariables were significantly associated with overall survival except GTV volume [hazard ratio (HR) of death per milliliter increase=1.019, 95% confidence interval (95% CI)=1.007-1.031, p<0.001], it remained the only statistically significant prognostic factor with adjusted HR of death of 1.028 (95% CI=1.001-1.055) (Table III). We found a GTV volume of approximately 70 ml may be used as a threshold for prognosis classification via running log-rank test using incremental volume of 10 ml (Figure 2).
Discussion
In this single-institute retrospective analysis, we found that radical definitive re-irradiation may lead to one-fifth long-term survivors for patients with OR of ESCC after previous curative radiotherapy, and GTV was the only significant prognostic factor for these patients.
Our results were somehow better than those reported in the recent systemic review, in which the highest overall survival rate reported was 12% at 3 years and 3% at 5 years (9, 14). Because this systematic review included articles up to June 2014, we searched PubMed using key words “((salvage radiotherapy) OR (salvage radiation therapy) OR (re-irradiation)) AND (esophageal cancer)” in Nov 2019 and identified four subsequent studies with sample sizes ranging from six to 55 (17-20). However, our 5-year overall survival rate was still higher than those of these four studies.
However, our results cannot be interpreted as definitive evidence to support the use of radical re-irradiation for patients after previous curative radiotherapy for ESCC because of potential bias due to our retrospective design. For example, PET was required to confirm OR in our study as used in a previous study (21), whereas PET was not mandatory in the above-mentioned studies (17-20). Furthermore, the advanced RT technology IMRT (22) was used in our study but not mandatory in the above-mentioned studies (17-20). These factors (use of PET and IMRT) may partly explain the impressive results seen in our study. However, our study was obviously not large enough for firm conclusions to be drawn. Furthermore, due to the lack for comparison group, RCT should be considered to compare radical re-irradiation with the current standard of care [systemic therapy] for this population. Other prospective studies such as ChiCTR1900020609 (23) or larger retrospective studies may also be helpful.
In conclusion, we found that radical definitive re-irradiation may lead to improved long-term survival rates for patients who have OR after previous curative radiotherapy for ESCC, and GTV was the only significant prognostic factor for these patients. Randomized controlled trials should be considered to compare radical re-irradiation with the current standard of care (systemic therapy) for this population.
Acknowledgements
This study was partially based on data from the China Medical University Hospital Cancer Registry.
Footnotes
↵* These Authors contributed equally to this work.
Authors' Contributions
Lin CY, Fang HY, Lein MY, Lin CC, Bai LY, Tsai MH, Chen CC, Hsieh TC, Wang YC, Liang JA and Li CC participated in the conception and design of study, interpreted data, and drafted the article. Chien CR participated in the conception and design of study, collected the related researches, analyzed and interpreted data, and drafted the article.
Conflicts of Interest
The Authors declare no conflicts of interest.
- Received February 27, 2020.
- Revision received March 16, 2020.
- Accepted March 17, 2020.
- Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
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