Clinical outcomes of definitive radiotherapy for patients with cT1aN0M0 esophageal cancer unsuitable for endoscopic resection and surgery
Introduction
Esophageal cancer (EC) is the eighth most common cancer worldwide and the sixth leading cause of death (1). Due to improvements in diagnostic procedures, the number of patients with superficial EC has been increasing. According to the Comprehensive Registry of Esophageal Cancer in Japan, the incidence rate of clinical stage I cancer among all patients with cancer increased from 23.1% in 1999 to 38.6% in 2013 (2).
Endoscopic resection is generally indicated for patients with tumors invading the lamina propria mucosa (LPM). Endoscopic resection or esophagectomy is the main treatment for patients with tumors invading the muscularis mucosa (MM) (3,4). However, in clinical practice, radiotherapy (RT) is often an alternative treatment for patients depending on their comorbidities, tumor localization, and extensive extension. Recently, results of some RT cases for clinical (c)T1bN0M0 EC have been reported (5,6). The outcomes of chemoradiotherapy (CRT) showed a trend toward non-inferiority in comparison with surgery in terms of overall survival (OS) in patients with cT1bN0M0 EC (6).
In Japan, several retrospective studies have shown promising clinical outcomes of definitive RT or CRT for stage I, including cT1aN0M0 EC (7-10). However, a few detailed reports discussed the recurrence patterns and subsequent salvage treatments, and efficacy from the point of view of organ preservation focused on cT1aN0M0. Therefore, this study aimed to clarify the clinical outcomes of definitive RT for cT1aN0M0 EC unsuitable for endoscopic resection and surgery. We present the following article in accordance with the STROBE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-21-773/rc).
Methods
Study population
This study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The retrospective study protocol was reviewed and approved by the Juntendo Hospital ethics review board (No. H20-0391). Informed consent was obtained in the form of opt-out on the Juntendo University website. Those who did not provide consent were excluded. We reviewed the medical records, RT treatment plans, and diagnostic images of patients with EC who underwent definitive RT or CRT in the Juntendo Hospital between January 2009 and December 2020. Eligibility criteria were as follows: (I) a pathologically proven esophageal squamous cell carcinoma; (II) Eastern Cooperative Oncology Group performance status (11) scores of 0–2; (III) cT1aN0M0 cancer based on the UICC-TNM Classification, Eighth Edition (12); and (IV) medically unsuitable for endoscopic resection and surgery. Patients who previously underwent endoscopic resection, surgery, RT, or chemotherapy for EC were excluded. EC was comprehensively diagnosed using physical findings, upper gastrointestinal endoscopy, and computed tomography. Magnifying endoscopy and endoscopic ultrasonography were used for the clinical diagnostic differentiation among T1a-epithelium (EP)/LPM, T1a-MM, and T1b-submucosa diseases in patients with EC (3). Comorbidities were estimated with the Charlson comorbidity index on the basis of 12 disease comorbidity categories (from 1 to 6 accordant with the relative risk of 1-year mortality) (13,14).
Treatment
External irradiation with 6 MV or 10 MV X-rays was performed with a linear accelerator; the daily dose of RT was 2.0 Gy based on the International Commission on Radiation Units of Measurement points, administered 5 days a week, for a total dose of 60 to 66 Gy. Either elective nodal irradiation (ENI), covering the bilateral supraclavicular and mediastinal lymph node regions, or involved-field irradiation (IFI) including the primary tumor with a margin of 2–4 cm was used. Three-dimensional conformal RT was performed for all patients. We used 2–4 fields to avoid the spinal cord. In patients who underwent two-field irradiation, the beam direction was changed after irradiation with 40 Gy. ENI was used in patients with normal respiratory and cardiac functions.
Chemotherapy was combined with RT in all patients, with the exception of those with poor general conditions. The chemotherapeutic regimen consisted of either 5-fluorouracil (5-FU; 700 mg/m2 on days 1–4 every 4 weeks) plus cisplatin (CDDP; 70 mg/m2 on day 1 every 4 weeks) or docetaxel (DOC; 10 mg/m2 on day 1 per week). The 5-FU plus CDDP regimen was used in patients with normal renal function, and the DOC therapy was used in elderly patients and patients with a declining renal function. After treatment completion, patients were followed up at 1- to 3-month intervals for the first 2 years and at 4- to 6-month intervals thereafter. Follow-up assessments included history taking and physical examination, blood test, upper gastrointestinal endoscopy, and computed tomography. A single radiation oncologist with expertise in esophageal cancer assessed the outcomes of this evaluation.
Outcomes
The initial response was measured based on the Response Evaluation Criteria in Solid Tumors guideline (version 1.1) (15) and using endoscopy findings for the primary tumor following the modified criteria of the 10th edition of the Japanese Classification of Esophageal Cancer established by the Japanese Society for Esophageal Disease. Complete response (CR) was defined as the disappearance of the primary tumor and irregular erosive lesions, ulcerative lesions, or apparently elevated lesions as observed during endoscopy and/or the absence of malignant cells in biopsy specimens (16). Conformation about patients who achieved CR was mandatorily obtained at least 1 month after CR was noted. Radiological imaging studies, upper gastrointestinal endoscopy, and medical records of physical examinations were used to identify the sites of recurrence. Metachronous recurrence was defined as the presence of recurrent lesions outside the primary site, and local recurrence was defined as the presence of recurrent lesions at the primary site. Salvage treatments conducted following recurrence were also assessed. Toxicity was assessed and documented following the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (17). Toxicities were defined as acute if they occurred within 3 months and as late if they occurred after 3 months post-treatment, respectively.
Statistical analyses
The OS and disease-specific survival (DSS) rates from the date of initiation of treatment were measured using the Kaplan–Meier method. Death from any cause was defined as an event to calculate the OS rate, and esophageal cancer-related death was defined as an event to calculate the DSS. Statistical analyses were performed with EZR version 1.54 (18).
Results
Patients’ characteristics
Between January 2009 and December 2020, 32 patients with cT1aN0M0 EC underwent definitive RT or CRT. Among these 32 patients, 12 had previously undergone endoscopic resection and the remaining 20 underwent definitive RT or CRT. Table 1 shows the patients’ characteristics. The patients who were unsuitable for endoscopic resection displayed spread of cancer along the entire tumor circumference (15 patients) and widespread tumor progression (6 patients) (including duplicates). The patients who were unsuitable for surgery displayed comorbidities (12 patients), double cancer (5 patients), and desire for esophageal conservation (7 patients) (including duplicates). Comorbidities included atrial fibrillation requiring anticoagulation in six patients, renal failure requiring dialysis in four patients, unstable angina requiring antiplatelet therapy in two patients, severe chronic obstructive pulmonary disease in two patients, and severe Parkinson’s disease in one patient (including duplicates). The median follow-up period was 50 months (range, 13–131 months) for the entire cohort and 55 months (range, 13–131 months) for 14 survivors. Among the 14 survivors, 3 patients were lost to follow-up.
Table 1
| Characteristics | Data |
|---|---|
| Age, years, median [range] | 70 [41–82] |
| Sex, n [%] | |
| Male | 13 [65] |
| Female | 7 [35] |
| ECOG PS score, n [%] | |
| 0 | 6 [30] |
| 1 | 13 [65] |
| 2 | 1 [5] |
| Location of the primary tumor, n [%] | |
| Cervix | 1 [5] |
| Upper thorax | 0 |
| Middle thorax | 15 [75] |
| Lower thorax | 3 [15] |
| Abdomen | 1 [5] |
| Invasion depth, n [%] | |
| EP | 0 |
| LPM | 11 [55] |
| MM | 9 [45] |
| Tumor craniocaudal length, mm, median [range] | 60 [20–160] |
| Tumor circumference, n [%] | |
| Entire | 15 [75] |
| ≥3/4 and < entire | 4 [20] |
| ≥1/2 and <3/4 | 1 [5] |
| Charlson comorbidity index, n [%] | |
| 2 | 8 [40] |
| 3 | 5 [25] |
| 4 | 4 [20] |
| 5 | 2 [10] |
| 6 | 1 [5] |
| Concurrent chemotherapy, n [%] | |
| None | 8 [40] |
| DOC | 11 [55] |
| FP | 1 [5] |
| Total radiation dose, n [%] | |
| 60 Gy | 18 [90] |
| 66 Gy | 2 [10] |
| Radiation field, n [%] | |
| ENI | 10 [50] |
| IFI | 10 [50] |
DOC, docetaxel; ECOG PS, Eastern Cooperative Oncology Group performance status; ENI, elective nodal irradiation; EP, epithelium; FP, 5-fluorouracil and cisplatin; IFI, involved-field irradiation; LPM, lamina propria mucosa; MM, muscularis mucosa.
Initial response and survival
All patients achieved CR at initial treatment. The 1-, 3-, and 5-year OS and DSS rates were 100% and 100%, 83% and 100%, and 67% and 100%, respectively (Figure 1). Among the six patients, three died of other cancers and the remaining three died of other causes, including chronic obstructive pulmonary disease (one patient) and aspiration pneumonia from cerebral infarction (two patients).
Toxicity
Table 2 shows toxicities associated with RT or CRT. Grade 3 acute esophagitis was noted in two patients (10%); grade 3 acute pneumonia in one patient (5%); grade 3 leukocytopenia in one patient (5%); grade 3 or worse late toxicities in none; and grade 4 or 5 toxicities in none.
Table 2
| CTCAE v5.0 | Grade 1 or 2 | Grade 3 |
|---|---|---|
| Acute toxicity, n [%] | ||
| Malaise | 5 [25] | – |
| Esophagitis | 17 [85] | 2 [10] |
| Dermatitis | 1 [5] | – |
| Pneumonitis | – | 1 [5] |
| White blood cell decreased | 9 [45] | 1 [5] |
| Anemia | 4 [20] | – |
| Decreased platelet count decreased | 4 [20] | – |
| Late toxicity, n [%] | ||
| Dysphasia | 2 [10] | – |
| Pleural effusion | 4 [20] | – |
| Pericardial effusion | 7 [35] | – |
| Pneumonitis | 3 [15] | – |
| Hypothyroidism | 3 [15] | – |
CTCAE, Common Terminology Criteria for Adverse Events.
Patterns of recurrence and salvage treatments
Table 3 shows a summary of patients with recurrence. Recurrence was observed in eight patients (local recurrence in six and metachronous recurrence in two). In two patients with metachronous recurrence, distances from the initial tumor to the metachronous recurrence were 50 and 60 mm, respectively.
Table 3
| Age, years | Sex | ECOG PS | Primary tumor location | Invasion depth | Tumor craniocaudal length (mm) | Tumor circumference | RT field |
RT dose (Gy) | CRT | Months to disease recurrence | Recurrence lesions |
Salvage therapy | Resected invasion depth | Resected tumor length (mm) | Resected Tumor circumference |
Status at last follow-up from salvage therapy (months) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 70 | Male | 1 | Mt | MM | 20 | Entire | IFI | 66 | No | 7 | Metachronous | APC | – | – | – | DID 22 |
| 61 | Male | 1 | Lt | LPM | 100 | Entire | IFI | 60 | Yes | 15 | Local | ESD | EP | 14 | <1/2 | ANED 104 |
| 65 | Male | 1 | Ae | LPM | 50 | Entire | ENI | 60 | No | 17 | Local | ESD | EP | 30 | <1/2 | ANED 16 |
| 62 | Male | 0 | Mt | MM | 30 | Entire | ENI | 60 | Yes | 17 | Local | ESD | EP | 5 | <1/2 | ANED 73 |
| 41 | Male | 0 | Mt | MM | 160 | Entire | ENI | 60 | Yes | 43 | Local | ESD | EP | 18 | <1/2 | ANED 44 |
| 73 | Male | 1 | Mt | LPM | 40 | Entire | IFI | 60 | Yes | 50 | Metachronous | ESD | LPM | 31 | <1/2 | ANED 32 |
| 72 | Male | 1 | Mt | MM | 100 | Entire | ENI | 60 | Yes | 55 | Local | ESD | EP | 12 | <1/2 | DID 7 |
| 49 | Female | 0 | Mt | MM | 150 | Entire | ENI | 66 | Yes | 80 | Local | ESD | EP | 8 | <1/2 | ANED 45 |
ANED, alive with no evidence of disease; APC, argon plasma coagulation; CRT, chemoradiotherapy; DID, died of intercurrent disease; ECOG PS, Eastern Cooperative Oncology Group performance status; ENI, elective nodal irradiation; EP, epithelium; ESD, endoscopic submucosal dissection; IFI, involved-field irradiation; LPM, lamina propria mucosa; MM, muscularis mucosa; RT, radiotherapy.
No lymph node and distant metastases were observed. After identifying recurrence, seven patients underwent salvage ESD and one underwent argon plasma coagulation (APC). Following endoscopic treatment, recurrence was not observed in any of the patients.
Discussion
The present study was designed to understand the clinical outcomes of definitive RT or CRT for patients with cT1aN0M0 EC unsuitable for endoscopic resection and surgery. In this study, the 5-year DSS rates were 100%. None of the patients died of treatment-related causes. All patients with recurrence were treated with salvage ESD or APC.
Table 4 enlists in detail the few previous studies that included patients with cT1aN0M0 EC. The CR rates in our study and in those conducted previously were favorable. Nemoto et al. and Ishikawa et al. reported that RT alone using IFI with or without intracavitary brachytherapy (ICBT) achieved 100% CR and demonstrated no regional lymph node recurrence (7,8). In our hospital, ENI was administered to patients with normal respiratory and cardiac functions a nd CRT with DOC was administered to older patients and patients with declining renal function owing to its radiosensitizing properties (19,20). However, CRT may cause severe hematologic toxicities (9). Previous studies reported fetal esophageal fistula with RT plus ICBT, whereas our study did not include any patient with severe esophageal fistula with RT or CRT (9,10). For stage II/III EC, the survival rate with CRT plus ICBT was not different from that of CRT alone (21). At present, ICBT, including palliative-intent treatment, is rarely performed for EC in Japan (3,22). The local recurrence rate in this study was slightly high as compared with those in previous studies (7-10). This might be associated with the longer tumor craniocaudal length in our study than in previous studies that reported that long tumor craniocaudal length was a prognostic factor for local recurrence of superficial EC, consistent with the findings of this study (8,23). All the patients who were unsuitable for endoscopic resection as the initial treatment because they displayed spread along the entire circumference or widespread tumor progression were treated with salvage ESD or APC. This can be attributed to the effect of regular follow-up with endoscopy. A previous study reported that patients with cT1–2 and N0 at baseline treated with salvage endoscopic resection showed significantly good prognosis in terms of OS (24). Regular follow-up with endoscopy and multidisciplinary treatment are considered important to manage cT1aN0M0 EC. Accordingly, CRT, ENI, and ICBT might be overtreatments for toxicities, and RT alone and regular follow-up with endoscopy for salvage endoscopic treatments might be an appropriate treatment for cT1aN0M0 EC.
Table 4
| Author | Year | No. | Age, years, median [range] | Sex (male/female) (%) | PS (0/1–2) (%) | Tumor craniocaudal length, mm, median [range] | Median prescribed dose, Gy | ICBT (yes/no) (%) | CRT (yes/no) (%) | Field ENI/IFI (%) | CR rate (%) | 5-year OS (%) | 5-year DSS (%) | Local recurrence (%) | Regional lymph node recurrence rate (%) | Distant metastasis (%) | Grade 3 esophagitis (%) | Grade 3–5 esophageal fistula (%) | Grade 3 leukopenia (%) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Nemoto (7) | 2001 | 52 | 68 [43–89]* | 85/15* | NS | NS | 65 | 63/37* | 3/97* | 0/100 | 100 | 62 | 81 | 12 | 0 | 0 | NS | NS | NS |
| Ishikawa (8) | 2006 | 18 | 70 [50–86]* | 89/11 | 39/61 | Almost <50 | 60–70 (range) | 33/67 | 0/100 | 0/100 | 100 | NA | 100 | 0 | 0 | 0 | 15* | 3* | NS |
| Yamada (9) | 2006 | 23 | 67 [48–83]* | 89/11 | NS | 36 [10–140]* | 59.8* | 100/0 | 100/0 | 0/100 | NS | NA | 85.2 | 17 | 0 | 0 | 3* | 3* | 21* |
| Murakami (10) | 2011 | 44 | 70 [43–89]* | 92/8* | 79/21* | Almost <30* | 54 | 61/39 | 0/100 | 100/0 | 98 | 84 | 97 | 29 | 2 | 0 | 2 | 3* | 1 |
| Our report | 2021 | 20 | 70 [41–82] | 65/35 | 30/70 | 60 [20–160] | 60 | 0/100 | 60/40 | 64/36 | 100 | 67 | 100 | 30 | 0 | 0 | 2 | 0 | 1 |
*, including submucosal cancer. CR, complete response; DSS, disease-specific survival; ECOG PS, Eastern Cooperative Oncology Group performance status; ENI, elective nodal irradiation; EP, epithelium; ICBT, intracavitary brachytherapy; IFI, involved-field irradiation; LPM, lamina propria mucosa; MM, muscularis mucosa; NS, not stated; OS, overall survival.
The current study has limitations associated with its retrospective design. First, the sample size was small; thus, statistical analysis was insufficient. Second, the external validity might be low. Some institutions performed subtotal-to-total circumferential resection with prophylactic steroids for more than 75% of the EC circumference (25,26). A phase III study aimed at prospectively evaluating the stenosis-preventive effect of submucosal triamcinolone injection and oral prednisolone treatment is ongoing (27). However, RT may be necessary for patients at high risk of esophageal stricture despite being treated with prophylactic steroids. Third, we could not demonstrate a difference in the appropriate treatment strategy between LPM and MM EC. Assessing the risk factors associated with metachronous lymph node or distant metastasis in patients treated with endoscopic resection revealed that the incidence of metastasis increased progressively with advancing depth of invasion. In a multivariate analysis, the depth of invasion was identified as the only significant risk factor, with a hazard ratio of 13.1 for pathological T1a-MM in comparison with pathological T1a-EP/LPM EC (28). CRT using ENI may be considered a definitive treatment for preventing regional lymph node recurrence in patients diagnosed with cT1a-MM EC. Therefore, a multicenter prospective study with a uniform strategy, such as EP/LPM EC for RT alone using IFI, is warranted.
In conclusion, definitive RT or CRT was considered an alternative initial treatment for patients with cT1aN0M0 EC who are contraindicated for endoscopic resection and surgery because no EC- and treatment-related deaths have been reported using salvage treatments. RT alone and regular follow-up with endoscopy for salvage endoscopic treatments might be appropriate treatment strategies for cT1aN0M0 EC.
Acknowledgments
We would like to thank Katherine Nixon for the help in polishing our paper.
Funding: None.
Footnote
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-21-773/rc
Data Sharing Statement: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-21-773/dss
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-21-773/coif). The authors have no conflicts of interest to declare.
Ethical Statement:
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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