|Year : 2016 | Volume
| Issue : 1 | Page : 62-68
Analysis of failure patterns in patients with resectable esophageal squamous cell carcinoma receiving chemoradiotherapy
Wen-Bin Shen1, Shu-Chai Zhu1, Hong-Mei Gao2, You-Mei Li1, Jin-Wei Su1, Juan Li1, Zhi-Kun Liu1
1 Department of Radiation Oncology, The Forth Hospital of Hebei Medical University, Shijiazhaung, China
2 Department of Radiation, The First Hospital of Shijiazhaung, Shijiazhaung, China
|Date of Web Publication||13-Apr-2016|
Department of Radiation Oncology, The Forth Hospital of Hebei Medical University, The 12th Jiankan Road, Chang'an District, Shijiazhaung - 050 011
Source of Support: None, Conflict of Interest: None
Purpose: This study investigates the failure pattern after chemoradiotherapy of patients with resectable esophageal squamous cell carcinoma (ESCC).
Materials and Methods: We retrospectively analyzed 92 patients with T1-2, N0-1, and M0 ESCC. These patients were inoperable because of poor performance, comorbidities, poor tumor region, or refusal of operation.
Results: Among the 92 patients, 29 cases displayed simple locoregional recurrence, 12 cases displayed simple distant metastasis, and 6 cases displayed distant metastasis with locoregional recurrence. Univariate analysis shows that the incidence of recurrence in the middle thoracic region was significantly higher than other regions (χ2 = 14.415, P = 0.001). For the 18 patients with distant metastasis, incidence of distant metastasis in the lower thoracic region was significantly higher than the other regions (= 39.359, P < 0.001). Among 35 cases with regional recurrence, 7 cases reached complete remission (14.6%) and 28 cases reached partial remission (PR; 63.6%) (χ2= 23.435, P < 0.001). Multivariate analysis shows that the patient age, tumor node metastasis (TNM) stage, and short-term efficacy were independent factors for locoregional recurrence. Patient age, TNM stage, X-ray length of the lesions, and short-term efficacy were the independent factors for distant metastases.
Conclusion: The incidence of locoregional recurrence and distant metastasis in patients with upper thoracic esophageal cancer was lower than those who had middle thoracic and lower thoracic esophageal cancer. The incidence of locoregional recurrence and distant metastasis in patients who achieved complete response after treatment was low.
Keywords: Chemoradiotherapy, esophageal squamous cell carcinoma, factor analysis, failure pattern
|How to cite this article:|
Shen WB, Zhu SC, Gao HM, Li YM, Su JW, Li J, Liu ZK. Analysis of failure patterns in patients with resectable esophageal squamous cell carcinoma receiving chemoradiotherapy. J Can Res Ther 2016;12:62-8
|How to cite this URL:|
Shen WB, Zhu SC, Gao HM, Li YM, Su JW, Li J, Liu ZK. Analysis of failure patterns in patients with resectable esophageal squamous cell carcinoma receiving chemoradiotherapy. J Can Res Ther [serial online] 2016 [cited 2019 Dec 6];12:62-8. Available from: http://www.cancerjournal.net/text.asp?2016/12/1/62/146128
| > Introduction|| |
Esophageal carcinoma is one of the most common cancers in the world with an estimated 482,300 new cases and 406,800 yearly deaths worldwide. Esophageal cancer is generally associated with poor outcomes. Despite an 11% improvement in survival over the past 30 years, 5-year survival rates for patients with localized, and regional involvement remain low at 33.7 and 16.7%, respectively. Surgery remains the main method for the treatment of early-stage thoracic esophageal cancer. However, for older patients who have poor cardiopulmonary functions or those with early-stage esophageal cancer who are unwilling to undergo surgery, radiotherapy combined with chemotherapy is the main treatment method. Randomized control trials show that survival rates obtained with this method are comparable with those obtained with surgical treatment, while simultaneously preserving the organs.,, Concurrent chemoradiation is the standard of care for esophageal carcinoma. Currently, the therapeutic effects and failure factors for advanced esophageal cancer patients who received chemoradiotherapy and the esophageal cancer patients who underwent surgery are analyzed in reports., Locoregional recurrence and distant metastasis are the main reason for treatment failure in patients with thoracic esophageal cancer.
Above all, analysis of the failure mode with esophageal cancer patients after treatment can guide the treatment method, so as to bring survival benefit for patients. At present, there are only a few reports are available on the detailed analysis of failure patterns of chemoradiotherapy for clinical early-stage esophagus cancer., In the present study, we analyzed the failure pattern of chemoradiotherapy in patients with clinically resectable esophageal cancer, the failure patterns of 92 cases of resectable esophageal cancer patients were analyzed. The results may provide a reference for accurate prognosis and therapy.
| > Materials and Methods|| |
A total of 92 patients with esophageal squamous cell carcinoma (ESCC) were diagnosed after a pathological examination in the Forth Hospital from February 2002 to July 2007. A written informed consent was obtained from all participants. All cases were treatment-naive and had complete hospitalization data, esophageal barium meal radiography, chest computed tomography (CT) scanning, and abdominal B ultrasound or CT examination. The esophageal barium meal radiography and chest CT films were rediagnosed in all patients treated with chemoradiotherapy by the doctors in the radiotherapy and radiology departments. All tumors were restaged according to the tumor node metastasis (TNM) staging system of the 2002 International Union against Cancer on the basis of physical examination and radiographic images. Considering the clinical staging standard, all patients in our study were in the T1-2N0-1M0 stage. All cases were considered clinically feasible for surgical resection. The patients in this group did not undergo previous surgery for the following reasons. A total of 41 patients had esophagus cancer at neck or upper thoracic region; 26 cases were elderly patients (70-86 years); 4 cases had cardiac insufficiency; 7 cases had pulmonary insufficiency; and 14 cases refused surgical treatment. Given that only three cases with cervical esophageal cancer were enrolled in our study, these cases were grouped as upper thoracic esophageal cancer. [Table 1] shows the general information of the patients.
Radiotherapy began on 1st day, concurrent with the beginning of cycle 1 of chemotherapy. The patients were fixed in position with a thermoplastic immobilizer, and simulation was performed with CT scan with 3 mm thickness (CT Brilliance, Philips Medical Systems, the Netherlands). The images were digitally transmitted and reconstructed into the 3D conformal treatment planning system (ADAC Pinnacle3 8.0 m, Philips Medical Systems, USA). Calculating dose corrections for inhomogeneity corrections in lung were automatically used in the treatment planning system. The lesion length was displayed by esophagography and fiber esophagoscopy, and the depth range was examined by CT scan. The enlarged lymph nodes were included in the gross tumor volume (GTV). The region extending from 0.5 to 0.8 cm from front, rear, left, and right sides; and 2.0-3.0 cm from the upper and lower sides of the GTV was designated as clinical target volume (CTV). The region extending from 0.5 to 1.0 cm uniformly from the CTV was designated as planning target volume (PTV). The adjacent tissues and organs, such as the spinal cord, trachea, heart, and bilateral lung, were simultaneously outlined. The optimal treatment plan was selected by dose–volume histogram and two-dimensional (2D) dose curves. Treatments were designed by using computerized radiation dosimetry and delivered by 6 MV X-rays from a linear accelerator (Elekta Precise Linear Accelerator, Sweden). All 92 patients accepted radical three-dimensional (3D) conformal radiotherapy. The PTV was covered by at least 95% isodose surface, and 95% of the PTV should receive 60 Gy of the prescribed dose. The maximum dose within the PTV was not allowed to exceed 110% of the prescribed dose. Each treatment plan consisted of a median of three static fields (range: 3-4) with the following normal tissue constraints: i) the mean lung dose (MLD) was ≤13 Gy, V5 (percentage of lung accepting 5 Gy dose) was ≤50%, V20 ≤ 25%, and V30 ≤ 20%; ii) the volume of heart receiving ≥40 Gy was ≤30%; and iii) the maximum spinal cord dose was ≤45 Gy. If these constraints cannot be satisfied, then the plan would be compromised with an MLD of <15 Gy, lung V20 ≤ 30%, and ≤40% of the heart volume receiving ≥40 Gy. The prescription dose was 60-70 Gy and was divided 30-35 times with 2 Gy once. The therapeutic course was 6-7 weeks, with a median dose of 64 Gy.
The concurrent chemotherapy consisted of 100 mg/m 2 of paclitaxel each cycle on days 1 and 8 plus 75 mg/m 2 of cisplatin on day 1 with adequate prehydration, mannitol, and antiemetic coverage by intravenous infusion every 3 weeks. Each cycle of chemotherapy was repeated every 3 weeks. Patients received an additional two cycles of chemotherapy after the completion of radiation with 1 month of rest. Antiemetic drugs were administered as required.
Evaluation of short-term efficacy and side effects
All patients successfully completed the therapeutic program. The follow-up was carried out at intervals of 1, 3, and 6 months after treatment. At least two follow-up per year were done for long-term survival patients. Chest CT/magnetic resonance imaging (MRI), esophageal barium meal radiography, and abdominal B ultrasound examination were carried out. Side effect was evaluated by using the radiation injury evaluation criteria of Radiation Therapy Oncology Group (RTOG). The following response criteria were employed for esophageal lesions. In complete remission (CR), the tumor completely disappeared. The esophagography showed that the esophageal edges were smooth, but the wall can be slightly stiff. In addition, the esophageal lumen was absent or slightly narrow (the ratio of the normal esophagus position compared with the narrow at the lesion site is 3:2). The esophageal mucosa returned to normal or was enlarged. In partial remission (PR), the tumor mostly disappeared, and no obvious distortion or tumor presence in a corner was observed. No ulcers were present outside the cavity, and the barium went through smoothly. Esophageal edges were smooth. A small filling defect and/or small niche was present or a smooth esophageal edge was observed. However, the lumen had obvious stenosis (the ratio of the normal esophagus position compared with the narrow at the lesion site is less than 3:2). In no remission (NR), no residual lesions or no evidence that lesions have improved markedly was observed. Significant filling defect, niche, or narrow was observed. Gastroscopy may be clear and effective, but not all of the patients can avail of this treatment, and positron emission tomography (PET)/CT is too expensive for patients in China.
Definition of the treatment failure patterns
Locoregional recurrence was defined as esophageal and/or regional lymph node failures. Once esophageal recurrence was suspected, a biopsy was required. When node recurrence was suspected; CT, MRI, or PET/CT should be performed. Lymph node recurrence was determined by one of the following criteria: (i) Nodes reappeared after complete disappearance; (ii) Nodes were enlarged after remaining stable; and (iii) New nodes of <1 cm in diameter appeared in the mediastinal or abdominal regions where no enlarged nodes existed prior to irradiation. Distant metastasis included distant node metastasis and distant organ metastasis. Distant node metastasis included M1a and M1b (UICC, 2002). M1a was referred to as supraclavicular or cervical lymph node metastases from the upper thoracic esophageal cancer or celiac axis nodes from the distal esophageal. M1b included all other patterns of distant nodal spread.
From end of December 2012, the patients were followed-up for 6-100 months, with a median of 34 months. The follow-up rate was 100%. The number of patients who were followed-up for 1, 3, and 5 years was 83, 45 and 31, respectively. Twenty-four patients are alive as of this writing.
Statistical Package for Social Sciences (SPSS) 11.5 statistical software was used for statistical analysis. The Kaplan–Meier method was applied in a single-factor analysis, and the significance test was carried out with double tail logrank method. Cyclooxygenase (COX) proportional hazards model was employed in a multifactor analysis, and the independent prognostic factors were evaluated with the backward Wald screening method (P < 0.05).
| > Results|| |
Among the 92 patients, 29 cases displayed simple locoregional recurrence, including 22 cases of esophageal recurrence in the field, three cases of esophageal recurrence outside the field, three cases of regional lymph node metastasis, and one case of original esophageal recurrence accompanied with regional lymph node metastasis. Twelve cases showed simple distant metastasis, including eight cases of organ metastasis and four cases of distant node metastasis. Six cases displayed distant metastasis accompanied with locoregional recurrence, including five cases of distant organ metastasis, one case of distant node metastasis, five cases of in situ esophageal recurrence, and one case of regional lymph node metastasis. The overall locoregional recurrence rate was 38.0% (35/92), and the overall distant metastasis rate was 19.6% (18/92). The details are shown in [Table 2]. The locoregional recurrence time was 2-90 months, with a median of 14 months. The distant metastasis time was 8-48 months, with a median of 19 months.
|Table 2: Summarized results of failure patterns in patients receiving the treatment|
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Univariate analysis of the failure patterns
Among the locoregional recurrence patients, the incidence of the middle thoracic recurrence was significantly higher than both upper and lower thoracic recurrences, with significant differences between them (χ2 = 14.415, P = 0.001). Among the distant metastasis patients, the incidence of distant metastasis in lower thoracic esophageal cancer patients was significantly higher than the upper and middle thoracic esophageal cancer patients, with obvious differences between them (χ2 = 39.359, P < 0.001). Among 35 cases of locoregional recurrence patients, the incidence of locoregional recurrence in T1 patients was lower than T2 patients, but no significant differences was observed between them (χ2 = 0.288, P = 0.591). The incidence of locoregional recurrence in N0 patients was lower than N1 patients, but no significant differences between them too (χ2 = 1.444, P = 0.230). Among 18 cases of patients with distant metastasis, the incidence of distant metastasis in T1 patients was lower than T2 patients, but no significant differences was observed between them (χ2 = 0.134, P = 0.714). The incidence of distant metastasis in N0 patients was lower than N1 patients, but no significant differences was observed between them too (χ2 = 1.552, P = 0.213). A total of 48 cases achieved CR and 44 cases achieved PR at the end of the treatment, and the overall effective rate was 100%. Among 35 cases with recurrence, there were seven patients in CR group (7/48, 14.6%) and 28 patients in PR group (28/44, 63.6%), and significant differences could be detected between them (χ2 = 23.435, P < 0.001). Among 18 cases of patients with distant metastasis, the incidence of distant metastasis in CR patients was lower than PR patients, but no significant differences was observed between them (χ2 = 1.583, P = 0.208). The details are shown in [Table 3].
COX multiple factor analysis
Single factors that may affect locoregional recurrence and distant metastasis, such as patient age, gender, lesion location, X-ray length of the lesions, GTV maximum transverse diameter, GTV length, GTV volume, PTV volume, clinical TNM stage, and short-term efficacy, were included in the COX multivariate regression model. Age, TNM stage, and short-term efficacy were independent factors for locoregional recurrence; whereas age, TNM stage, X-ray length of the lesions, and short-term efficacy were the independent factors for distant metastases. The details are shown in [Table 4] and [Table 5].
Analysis of therapeutic efficacy
The 1-, 3-, and 5-year overall survival rates of all patients were 88.0, 47.8, and 35.7%, respectively, with a median of 33 months. The 1-, 3-, and 5-year regional control rates were 83.3, 65.7, and 60.1%, respectively. The 1-, 3-, and 5-year distant metastasis-free survival rates were 85.9, 45.7, and 34.8%, respectively. The 1-, 3-, and 5-year tumor-free survival rates were 76.1, 44.4, and 33.1%, respectively. A total of 25 cases of lymph node metastasis prior to treatment were observed, including one case of left supraclavicular lymph node metastasis, two cases of right supraclavicular lymph node metastasis, and 22 cases of mediastinal lymph node metastasis. After the treatment, nine cases achieved CR and three cases showed regional mediastinal lymph node metastasis, including one case of right supraclavicular lymph node metastasis.
| > Discussion|| |
Regional recurrence and distant metastasis are two main failure patterns of esophageal cancer therapy. To solve this problem, many cancer treatment centers have conducted related studies; however, no satisfactory result was found., We report on our institution's experience with esophageal cancer, examining survival outcomes and patterns of disease recurrence after chemoradiotherapy. In our study, none of the patients received elective nodal irradiation (ENI). Our results showed 35 cases (38.0%) of locoregional recurrence and 18 cases (19.6%) of distant metastases among the 92 patients who received chemoradiotherapy. The 35 cases of locoregional recurrence included 27 cases of recurrence within the irradiation field, 8 cases of recurrence outside the irradiation field, and 1 case of recurrence within the irradiation field accompanied by regional lymph node metastasis. These results were consistent with our previous reports and were consistent with majority of the previously mentioned reports.,, Conducting involved field irradiation (IFI) 3D-conformal radiotherapy for early resectable esophageal cancer was feasible, and the locoregional recurrence rate did not increase in patients.
Multiple forms of locoregional recurrence and metastasis for esophageal cancer patients are observed after treatment. In this study, the locoregional recurrence was divided into regional esophagus recurrence and regional lymph node metastasis, and the distant metastasis was divided into distant organ hematogenous metastasis and distant lymph node metastasis at different esophageal lesion locations. Few reports discussed the factors affecting regional recurrence and distant metastasis. Yamashita et al., found that the regional recurrence rate at the upper thoracic esophagus was significantly lower than that of the middle and lower thoracic esophagus, after an analysis of 126 patients with esophageal cancer. Denham et al., conducted an analysis study in 274 patients with esophageal cancer. They showed that the recurrence and distant metastasis rates of upper thoracic esophagus were significantly lower than that of the middle and lower thoracic esophageal cancer; whereas, the recurrence and distant metastasis rates of patients without residual cancer after treatment were significantly lower than those with residual cancer. In the present study, the single-factor analysis showed that the efficacy for the upper thoracic esophageal cancer was better than those for the middle and lower thoracic esophageal cancers, with lower regional recurrence rate and distant metastasis rate. The reasons for the low recurrence rate of upper thoracic esophageal cancer may be related to the following. (i) Clinical symptoms appeared earlier, and patients were diagnosed easily. (ii) The tumor is in a relatively fixed position, which is favorable for treatment. (iii) The tumor volume is relatively small. (iv) The radiation dose is high. Results of our study also indicated that the locoregional recurrence rate of patients who achieved CR after treatment was significantly lower than those who achieved PR. Majority of clinical studies indicated that tumor recurrence was related to the tumor stage and the pathological and biological behavior of the tumor.,,,,, The clinical staging of esophageal cancer is not as convincing as the postoperative pathological staging is; however, preoperative clinical staging is also feasible with the development of treatment technology and the diversity of examination methods. Our multivariate analysis results showed that patient age, clinical N staging, clinical TNM staging, and short-term efficacy were the independent prognosis factors affecting the regional recurrence and distant metastasis in patients. In addition, the X-ray length of lesions was an independent prognosis factor for patient distant metastasis. Our findings were consistent with the above reports.,,,,,,, Our result also showed that age was an independent factor affecting the incidence of regional recurrence and distant metastasis. The possible reason is that the patients in our group were in an early clinical stage, so the survival rate of them was relatively long; and also the survival rate of patients with recurrent and/or transfer is also likely to increase. The patient's age is also older in our study; there are 43 patients (46.7%) ≥70 year. The dose of radiotherapy and chemotherapy are generally conservative for elderly patients, which may affect their curative effect.
A satisfactory solution for treating the recurrence and distant metastasis after the initial treatment of esophageal cancer is unavailable. Some reports considered 3D conformal radiotherapy to be feasible for regional recurrence of esophageal cancer after the initial radiotherapy, with good clinical remission rate and immediate efficacy. Fakhrian et al., analyzed the feasibility and effectiveness of radiotherapy in the management of 54 recurrent esophageal carcinoma patients with a median dose of 45 Gy (range 30-68 Gy). The survival rates at 1, 2, and 3 years were 55 ± 7, 29 ± 6, and 19 ± 5%, respectively. They thought that RT is feasible and effective in the management of recurrent esophageal carcinoma, especially for relief of symptoms. Toxicity is in an acceptable range. And long-term survival of patients with recurrent esophageal carcinoma after radiochemotherapy might be possible, even with a previous history of radiotherapy in the initial treatment. If re-irradiation (re-RT) of esophageal carcinoma is contemplated, 3D conformal techniques and a minimum total dose of 45 Gy are recommended. Some patients could achieve prolonged survival period. However, the complications of repeating radiotherapy was high, and the indications should be strictly controlled during clinical applications. Kim et al., evaluated the toxicities and clinical outcomes of re-RT for 10 recurrent esophageal cancer patients. The total dose of re-RT was a median of 46.5 Gy (range 44.0-50.4 Gy). Their results showed that two patients were complete response, one was partial response, two were stable disease, and five were progressive disease after the end of re-RT. Grade 5 tracheoesophageal fistula developed in three patients, late toxicities included grade 1 dysphagia (n = 1). So they thought that re-RT of recurrent esophageal cancer after primary radiotherapy can cause severe toxicity. With the continuous update of anticancer drugs and the development of radiotherapy technology, recurrent patients may be benefited to some extent. Nonoshita et al., assessed the feasibility, efficacy, and complications of high dose rate (HDR) brachytherapy (Ir-192 source) for six patients with recurrent esophageal cancer after external radiotherapy. All patients underwent HDR brachytherapy once a week with a dose of 4 or 5 Gy per fraction in the esophageal mucosa (median total dose 20 Gy), their results showed that local control was observed in five patients and residual tumor in one patient, persistent local control was observed in two patients, no patient died of esophageal cancer, and no severe late complications related to HDR brachytherapy. So they thought that HDR brachytherapy is an effective and safe treatment for patients with recurrent esophageal cancer after external radiotherapy. In addition, surgical treatment can be considered a therapeutic method for patients with regional recurrence.
Locoregional recurrence and distant metastasis are still the main failure patterns in patients with esophageal cancer after treatment, and no definite solution exists. Close follow-up and active subsequent treatment for high-risk groups of locoregional recurrence and distant metastasis should be done for future clinical practice in elderly patients, patients with esophageal cancer at the middle and lower thoracic regions, patients with long lesions, patients who failed to achieve CR after treatment, and patients with late-stage cancer.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]