Abstract
Background/Aim: We compared the outcome of docetaxel, cisplatin, and 5-fluorouracil as combination chemoradiotherapy (DCF-RT) for unresectable locally advanced thoracic esophageal cancer (EC) with that of cisplatin (CDDP) and 5-fluorouracil (5-FU) as combination chemoradiotherapy (CF-RT) in clinical settings. Patients and Methods: Seventy-three patients with unresectable locally advanced thoracic EC were included in this study. CF (n=38) consisted of intravenous CDDP at 70 mg/m2 (day 1) and 5-FU at 700 mg/m2 (days 1 to 4), repeated every four weeks for two cycles. DCF (n=35) consisted of intravenous docetaxel at 50 mg/m2 (day 1), CDDP at 60 mg/m2 (day 1), and 5-FU at 600 mg/m2 (days 1 to 4), repeated every four weeks for two cycles. Patients were irradiated with 60 Gy in 30 fractions. Results: The overall complete response (CR) rate of DCF-RT was significantly higher than that of CF-RT (36.7% vs. 3.7%, p=0.003). The 3-year overall survival (OS) rate of DCF-RT was significantly higher than that of CF-RT (32.8% vs. 8.5%, p<0.001). Conclusion: DCF-RT demonstrated a higher CR rate and OS for unresectable locally advanced thoracic EC than CF-RT.
Esophageal cancer (EC) is the 6th leading cause of death from cancer and the 8th most common cancer worldwide. The 5-year survival ranges from 15%-25% (1). Concurrent chemoradiotherapy (CRT) is the standard therapy for unresectable esophageal cancer. Definitive CRT may also be a treatment option for patients who refuse or cannot tolerate surgery (2). The most employed regimen with concurrent radiation therapy for esophageal cancer is cisplatin and 5-fluorouracil (CF-RT) (3-5). However, this regimen’s outcome remains unsatisfactory in terms of local control, toxicity, and survival rate (5-7). Thus, more effective regimens are needed to improve patients’ prognosis with esophageal cancer. We previously reported that docetaxel, cisplatin, and 5-fluorouracil in combination with radiotherapy (DCF-RT) led to a high complete response (CR) rate and a favorable prognosis compared with standard chemoradiotherapy for advanced esophageal cancer (8). DCF-RT has been administered in clinical settings based on the results of several phase I/II studies (8-10). DCF-RT has also been reported to result in better overall survival (OS) and CR rates than CF-RT (11). However, previous studies about DCF-RT for advanced EC included patients at various cancer stages; thus, efficacy of DCF-RT for unresectable locally advanced EC without distant metastases is unclear. Therefore, we performed a retrospective analysis of patients with unresectable locally advanced thoracic EC without distant metastasis who received definitive DCF-RT to evaluate the outcome of DCF-RT in a real-world clinical setting. We also compared the efficacy of DCF-RT to that of CF-RT in our historical cohort.
Patients and Methods
Patients. This retrospective study was approved by the ethics committee of the Graduate School of Medicine, Gunma University (Protocol number HS2019-319). Informed consent was obtained in the form of opt-out on the website. The study subjects comprised 73 patients with unresectable locally advanced thoracic EC treated by CF-RT (from May 1998 to December 2007) and DCF-RT (from July 2008 to December 2015) at our institute. Sixteen patients of DCF-RT had been enrolled in the previous phase II study (8). Exclusion criteria were distant organ metastasis, synchronous cancer, pretreatment chemotherapy, and different radiation protocol [treated by intensity-modulated radiation therapy (IMRT) boost after the initial 40 Gy]. Hospital patient records were reviewed for tumor characteristics and patient outcomes. The tumor stage and disease grade were classified according to the 8th edition of the TNM classification of the International Union Against Cancer (UICC) (12). The tumor stage was determined conventionally using computed tomography (CT) and positron emission tomography (PET)-CT of the neck, chest, and abdomen, endoscopic ultrasonography (EUS), endoscopy, and esophagography.
Treatment. Patients received concurrent radiotherapy and chemotherapy for six weeks after the diagnostic procedures. In the CF-RT, chemotherapy consisted of intravenous cisplatin (CDDP) at 70 mg/m2 on day 1 and intravenous 5-FU at 700 mg/m2 on days 1 to 4, repeated every four weeks for two cycles. In the DCF-RT, chemotherapy consisted of intravenous docetaxel at 50 mg/m2 on day 1, intravenous CDDP at 60 mg/m2 on day 1, and intravenous 5-FU at 600 mg/m2 on days 1 to 4, repeated every four weeks for two cycles. Patients were irradiated with 1.8 to 2.0 Gy/fraction using 10-MV photons from a linear accelerator. The initial 40 Gy dose was delivered to the initial radiation field involved the primary tumor and lymph node region with metastasis using anterior-posterior opposed fields. The boost dose of 20 Gy was delivered to the shrinked primary tumor and metastatic lymph nodes using oblique parallel opposed fields to avoid the spinal cord. In DCF-RT, radiation was administered using 3-dimensional conformal radiotherapy (3D-conformal RT). Patients judged to be resectable at 30-40 Gy irradiation were considered for switching to esophagectomy and regional lymph node dissection 3 or 4 weeks after irradiation up to 40 Gy (conversion surgery).
Response evaluation. Standard clinical measurements and radiological examinations were used to assess the tumor response according to RECIST. The treatment response of the primary lesion (non-target lesion) was evaluated according to the Japanese Classification of Esophageal Cancer, 11th edition (13). One month after completing treatment, the first evaluation of the initial tumor response was carried out. The second evaluation was carried out more than 4 weeks from the first evaluation. Endoscopy was repeated to confirm primary complete response (CR) and progressive disease. Response evaluation was performed except in conversion surgery (CF: n=11, DCF: n=5).
Toxicity. Toxicities were assessed using the Common Terminology Criteria for Adverse Events v4.0. An adverse event developing more than 90 days after CRT was defined as late toxicity.
Follow-up. Patients were assessed every three months after treatment completion for the first two years and six months thereafter. CR was confirmed by endoscopy, biopsy specimens, CT, and PET-CT. For patients who underwent conversion surgery, follow-up was generally performed in 3- to 4-month intervals within the first two years after surgery and every six months until five years.
Statistical analysis. Locoregional failure was defined as the persistence or recurrence of the primary tumor or regional lymph nodes. Distant failure was defined as metastasis to any site beyond the primary tumor and regional lymph nodes. Subject characteristics were compared using chi-squared tests for categorical variables and the Student’s t-test for continuous variables. Overall survival (OS) was calculated from the start of treatment to the last follow-up or death. Kaplan–Meier curves were generated for OS and PFS. All analyses were performed using R version 2.13.0 (The R Foundation for Statistical Computing, Vienna, Austria) statistical software.
Results
Patient characteristics. The patient characteristics are detailed in Table I. Twenty-one patients with supraclavicular lymph node metastasis were categorized as M1 (Lym). Sixteen patients underwent conversion surgery. The median follow-up period of survivors was 36.8 months (range=4-115.5 months).
Patient characteristics.
Treatment outcome of DCF-RT. The relative dose intensity in the first cycle of DCF was 95.9% for all patients, and that in the second cycle of DCF was 67.4%, excluding five patients who underwent conversion surgery. The overall and local CR rates were 36.7% [95% confidence interval (CI)=19.9-56.1] and 53.3% (95%CI=34.4-71.7), respectively. The 3-year OS rate of DCF-RT was 32.8% (95%CI=17.6-48.9). Twenty-two patients (62.9%) died from cancer, and one (2.9%) died from a non-cancer-related cause within five years from the start of treatment. Excluding five conversion surgery cases, the 3-year OS was 31.3% (95%CI=15.3-48.8).
Failure pattern and salvage treatment of DCF-RT. The initial failure pattern and salvage treatment excluding the 5 cases of conversion surgery were as follows: Twenty-six patients (86.7%) had a recurrence or residual disease of any type at the time of analysis. In these patients, locoregional failure was 17 (56.7%), and distant failure was 9 (30.0%). Among the 17 patients with locoregional failure, 3 patients underwent salvage lymphadenectomy without severe complications. Of the remaining 14 patients with locoregional failure, 7 received chemotherapy, and 7 had no further anticancer treatment. Among the 9 patients with distant failure, 2 had node recurrence outside the elective nodal irradiation area [accessory nerve lymph node (n=1) and hilar (n=1)]. The remaining 7 patients had distant organ metastases [lung (n=3), liver (n=1), bone and lung (n=1), peritonitis and pericarditis (n=1), adrenal gland, skin, and brain (n=1)]. One patient with lung metastasis underwent salvage resection of the metastasis. Among the 5 patients who underwent conversion surgery, 2 had distant metastasis, and one had locoregional recurrence after surgery.
Toxicities of DCF-RT. The acute toxicity profile is presented in Table II. The most frequently observed grade 3 and 4 acute toxicities were leucopenia, neutropenia, and anorexia. The late toxicity profile is presented in Table III. Thirty patients, excluding the 5 patients of conversion surgery, were available to evaluate late toxicities. The most frequently observed grade 3 or 4 late toxicities were pleural effusion, pericarditis, and esophageal stenosis. The rate of any grade 3 or 4 late toxicity was 10.0%. One (3.3%) patient was considered to have died of treatment-related late toxicity. The cause of death was chronic empyema developed subsequently to pleural effusion [cT3N0M0 (n=1)]. There was no evidence of residual or recurrent disease in the patient.
Acute toxicity of docetaxel/CDDP/5FU-radiotherapy.
Late toxicity of docetaxel/CDDP/5FU-radiotherapy.
Comparison of efficacy between CF-RT and DCF-RT. The overall CR rate of CF-RT was 3.7% (95%CI=0.1-19.0). The overall CR rate of DCF-RT was significantly higher than that of CF-RT (p=0.003) (Table IV). The 3-year OS rate of CF-RT was 8.5% (95%CI=2.2-20.3). The OS rate of DCF-RT was significantly higher than that of CF-RT (p<0.001) (Figure 1).
Comparison of overall CR rate between CF-RT and DCF-RT.
Kaplan–Meier curves for overall survival (OS) according to the treatment regimen.
Discussion
In this study, the OS and CR rate for patients with unresectable locally advanced thoracic EC who underwent DCF-RT were higher than those who underwent CF-RT. To the best of our knowledge, this is the most extensive cohort study investigating the outcome of unresectable locally advanced thoracic EC patients without distant organ metastasis undergoing DCF-RT in the real-world clinical setting.
The CR rates of DCF-RT (36.7%) were superior to those of CF-RT (3.7%) in our study, also being superior to that in the previous CF studies for advanced EC (5, 14). Our study further supports existing data showing an improved response rate of DCF-RT (9, 11). One possible reason for those improved CR rates was the addition of docetaxel to CF-RT. Docetaxel has been reported to be a potent enhancer of tumor radioresponse (15). Another reason for the improved CR rate in this study could be the total dose of 60 Gy in radiotherapy for EC. The dose of 60 Gy in our study may be excessive, considering the results of the RTOG94-05 study (16). However, a previous meta-analysis reported that high-dose (≥60 Gy) radiotherapy as definitive CRT improves survival compared with standard-dose radiotherapy in patients with esophageal SCC (17). The total dose of 60 Gy is often used in Asian countries where squamous cell carcinoma (SCC) is the predominant histological type. These findings support our improved response rate.
The dominant initial failure pattern of DCF-RT was a locoregional failure in our study, similar to that in previous DCF studies (62.9-72.0%) (9, 11). The dominance of the locoregional failure rate in our study reflects the inclusion of patients with advanced T stage. The distant failure rate (30.0%) of DCF-RT in our study was better than those of a previous study of CF-RT for cT4 patients (39.8%) (18). The results indicated that DCF-RT has a better effect not only on local control but also on preventing distant metastasis.
Previous prospective studies reported that the 2-year and 3-year OS of CF-RT for unresectable thoracic EC were 31.5% (5) and 25.9% (14). Recently, several groups reported the improved 3-year OS (43.9-56.7%) of advanced EC patients treated by DCF-RT (9, 11). However, those CF-RT and DCF-RT studies included non-T4 EC. Our study included only T4 EC and demonstrated the OS of patients treated by DCF-RT to be superior to that of FP-RT in the historical cohort. Furthermore, the OS of patients treated by DCF-RT in our study seemed to be superior to those in previous CF-RT studies (5, 14). Thus, our results appropriately suggested that DCF-RT was a more promising treatment regimen for unresectable locally advanced thoracic EC than CF-RT,, even in clinical settings.
The myelotoxicity of DCF-RT was higher than that of CF-RT (5, 19) among acute toxicities. The incidence rates of grade 3 and 4 leukopenia (68.6%) and neutropenia (60.0%) were similar to those in previous DCF studies (9-11). In our study, severe myelosuppression or late recovery from myelosuppression was mainly the reason for a decrease in relative dose intensity from 95.9% in the first cycle to 67.4% in the second cycle. Prevention and precise management of these hematological toxicities are necessary for safe DCF-RT completion. Whether the prophylactic use of long-acting G-CSF agents increase the dose intensity must be further investigated.
Late toxicity after CRT can result in severe, life-threatening complications. In this study, the rate of any grade 3 or 4 late toxicity of DCF-RT was 10.0%, comparable with that in a previous study (9). In our study, one (3.3%) patient who underwent DCF-RT was considered to have died of treatment-related late toxicity with no evidence of residual or recurrent disease. Long-term follow-up is necessary even for patients achieving CR after DCF-RT.
This study has several limitations. First, there was a selection bias because this study was a retrospective single-institution analysis. Second, due to the regimen’s transition during the study period, we were forced to use the historical cohort to compare the efficacy between CF-RT and DCF-RT. Further multicenter, large-population-based investigations are needed to confirm the effects of advances in DCF-RT for unresectable locally advanced thoracic EC. In conclusion, DCF-RT demonstrated a higher CR rate and OS for unresectable locally advanced thoracic EC than CF-RT.
Footnotes
Authors’ Contributions
Study conception and design: Sakai, acquisition of data: Saito, Nakazawa, Ubukata, Kuriyama, Hara, analysis and interpretation of data: Sakai, Sohda, Sano, Ogawa, Yokobori, Murata, Noda, drafting of manuscript: Sakai, critical revision: Ohno, Shirabe, Saeki.
Conflicts of Interest
The Authors have no conflicts of interest to declare in relation to this study.
- Received February 16, 2021.
- Revision received February 26, 2021.
- Accepted March 1, 2021.
- Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.