The present study aimed to assess the feasibility of global standard chemoradiotherapy (CRT) followed by surgery in patients with esophageal cancer. A prospective study was conducted at Nagoya University Hospital (Nagoya, Japan) to evaluate global standard CRT followed by surgery in patients with esophageal cancer. The CRT regimen consisted of 75 mg/m2 cisplatin on day 1 and 1,000 mg/m2 fluorouracil daily on days 1-4 given twice 4 weeks apart together with concurrent esophageal irradiation starting on day 1 (group A). For comparison, 17 patients with esophageal cancer who had received the same chemotherapy regimen but with lower drug doses were retrospectively reviewed: 70 mg/m2 cisplatin on day 1 and 700 mg/m2 fluorouracil daily on days 1-4 given twice 4 weeks apart together with concurrent esophageal irradiation starting on day 1 (group B). Grade 3 or worse adverse events were observed in 9 of the 12 patients (75%) in group A and in 5 of the 17 patients (29%) in group B. The patients in group A were more likely to experience grade 3 or worse neutropenia (50%) than those in group B (6%). No febrile neutropenia or treatment-related deaths occurred in either group. A total of 11 patients (92%) in group A and 16 patients (94%) in group B subsequently underwent an esophagectomy, and 9 (82%) and 14 (88%) of these patients, respectively, achieved microscopically margin-negative resection (R0 resection). In conclusion, global standard CRT was more likely to cause severe but manageable adverse events. There was no apparent difference in the R0 resection rate or postoperative complications between the two treatments. This clinical trial was registered at the Japan Registry of Clinical Trials (trial registration number: jRCT1041180004) on September 11, 2018.
Preoperative chemoradiotherapy (CRT) followed by surgery is a global standard treatment for resectable esophageal cancer (
We conducted a prospective study in which patients with resectable esophageal cancer received global standard CRT followed by surgery in a university hospital in Japan. The study was designed and conducted in line with the Helsinki Declaration and the Ethical Guidelines for Clinical Research (Ministry of Health, Labor and Welfare, Japan). It was approved by the Institutional Review Board (approval no. 2018-0453) and registered at the Japan Registry of Clinical Trials (jRCT1041180004). All participants provided written informed consent before study enrollment.
The main eligibility criteria included i) histologically confirmed esophageal squamous cell carcinoma or adenocarcinoma or adenosquamous carcinoma or basaloid cell carcinoma; ii) Stage I B, Stage II, Stage III (T4 included), or Stage IV (only supraclavicular lymph node metastasis included); iii) Eastern Cooperative Oncology Group performance status (PS) 0-1; iv) preserved organ functions; v) age 20-75 years; vi) with or without measurable lesion; and vii) no prior treatment for esophageal cancer.
The patients first received global standard CRT consisting of 75 mg/m2 cisplatin on day 1 plus 1,000 mg/m2 fluorouracil daily on days 1 through 4, given twice 4 weeks apart (2 courses) together with concurrent irradiation for the esophagus starting on day 1 (1.8 Gy once daily in 23 fractions, a total of 41.4 Gy) and then underwent surgery. All AEs were evaluated according to the Common Terminology Criteria for Adverse Events v 4.0 (CTCAE). Treatment was continued until unacceptable AEs or disease progression occurred. The cisplatin doses for the first and the second courses were reduced based on the patient's creatine clearance calculated using the Cockcroft-Gault equation (
Initially, the primary endpoint was the objective response rate (RR), and a total of 21 patients were planned to be enrolled. The planning sample size was estimated based on a threshold RR of 40%, an expected RR of 75%, a 5% significance level (one-sided), and 90% power, given 10% of patient discontinuation or loss. However, because the study was closed when 12 patients were enrolled due to slow patient enrollment, the results of the study were analyzed primarily from the viewpoint of feasibility. Clinical response was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. (
Relative dose intensity (RDI) was calculated as the ratio of the total actual dose intensity (DI) to the total planned DI. RDI and DI were defined as follows: DI=total actual dose (mg/m2)/total time to complete therapy (weeks); RDI (%)=(DI of actual therapy/DI of the planned regimen) x100.
We retrospectively reviewed 17 patients under the age of 75 with the same disease between January 2018 and December 2021 who had received the same CRT as patients in the prospective study except for a chemotherapy regimen with lower drug doses (approval no. 2022-0191). The chemotherapy regimen was 70 mg/m2 cisplatin on day 1 plus 700 mg/m2 fluorouracil daily on days 1 through 4. Dose reduction or interruption was left to the discretion of the attending physicians. Prophylactic antiemetics, therapeutic G-CSF, and antibiotics were used according to the relevant clinical guidelines. Prophylactic G-CSF was not used.
All the patients in both groups received standard clinical care, including esophagectomy and chemotherapy in case of recurrence.
Statistical analysis was performed using IBM SPSS Statistics version 28.0 (IBM Japan Ltd., Tokyo, Japan). The P-value for age between two groups was calculated using the Mann-Whitney U test, whereas those for other factors were calculated with Fisher's exact test. P<0.05 was considered to indicate statistical significance. Kaplan-Meier curves and the log-rank test were used to analyze and compare survival between the two groups.
Between September 2018 and January 2022, 12 patients were enrolled in the study (
All the patients experienced hematological or nonhematological AEs during CRT (
Eleven patients [91.7; 95% confidence interval (CI): 61.5-99.8%] subsequently underwent an esophagectomy, of which 9 (81.8; 95% CI: 48.2-97.7%) achieved microscopically margin-negative resection (R0 resection). The remaining patient underwent esophageal bypass surgery due to disease progression. The histopathological responses of the 11 patients who underwent esophagectomy were grade 1a in two, grade 1b in two, grade 2 in five, and grade 3 in two. Regarding postoperative complications, four patients experienced grade III or worse lung infection (
There were no significant differences in the patients' background characteristics between the two groups (
The most common AEs of any grade were anemia and hypoalbuminemia, which occurred in all patients (
Sixteen patients (94.1%; 95% CI: 71.3-99.9) received an esophagectomy, which achieved R0 resection in 14 (87.5%; 95% CI: 61.7-98.4%). The other patient (the seventeenth) received esophageal bypass surgery due to lung metastasis. The histopathological responses of the 16 patients who underwent esophagectomy were Grade 1b in six patients, Grade 2 in six, and Grade 3 in four. The most common grade III or worse postoperative complications was lung infection in five patients (
We compared RFS between groups A and B (
This study assessed the feasibility of global standard CRT followed by surgery in Japanese patients with esophageal cancer by comparing results from the prospective study with the global standard chemotherapy regimen (group A) to those from past cases treated with the low-dose regimen (group B). Apparently, the patients treated with the global standard regimen were more likely to experience grade 3 or worse AEs, particularly neutropenia, than those treated with the low-dose regimen. However, as expected, the AEs that occurred in the patients who received the global standard regimen were manageable, and there were no FN- or treatment-related deaths. On the other hand, there appeared to be no apparent difference in R0 resection rates and postoperative complications between the two treatments.
The overall mean RDIs of cisplatin and fluorouracil in group A were higher than those in group B. In particular, there was a large difference in the DI of fluorouracil (97% vs. 69%). Although there were no apparent differences in the R0 resection rate and possibly survival between the global standard and low-dose regimens, there was a tendency that OS was possibly better with a global standard regimen, and the difference may be obvious when larger numbers of patients are analyzed. Given the feasibility of the global standard regimen, it is reasonable to recommend preoperative CRT with global standard-dose chemotherapy in Japanese patients with esophageal cancer.
There were some limitations in the present analysis. First, because the number of patients in each group was too small to objectively conclude that a global standard dose of cisplatin and fluorouracil is feasible and could provide survival benefit, to verify the survival differences with different doses of cisplatin and fluorouracil, a randomized study with a larger patient sample is needed in the future. Second, the present study was not randomized and was controlled with a historic sample set. Nevertheless, because the patients in the two groups had similar backgrounds, they were considered to be comparable. Third, because dose reduction or interruption was based on the discretion of the attending physicians, it could bring favorable results for AEs in group B. Despite the limitations, the global standard CRT followed by surgery was suggested to be feasible and should be recommended in Japanese patients with esophageal cancer. However, further discussion or more data is needed to support the conclusion.
In conclusion, the global standard regimen was manageable, although potentially associated with more adverse events when compared to the low-dose regimen. The difference in R0 resection rates was not apparent, possibly due to the small number of patients in both groups. Differences in RFS and OS also need to be examined in a larger sample of patients.
Not applicable.
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
OM designed the study. KM, MiK, DS, SS, TO, JI, MaK, SI, YK and YA conducted the clinical trial and provided clinical data. OM and YA confirmed the authenticity of all the raw data. MN and MA performed the statistical analysis. YL and OM analyzed the data and wrote the manuscript. OM, YK and YA revised the manuscript. All authors read and approved the final manuscript.
This study was approved by the Institutional Review Board of Nagoya University Hospital (approval nos. 2018-0453 and 2022-0191). All participants of the prospective study (jRCT1041180004) (Group A) provided written informed consent before enrollment in the study. Informed consent for the retrospective analysis (Group A and Group B) was obtained in the form of opt-out at the website.
All participants of the prospective study (jRCT1041180004) (Group A) provided written informed consent for publication. Informed consent for publication for the retrospective analysis (Group A and Group B) was obtained in the form of opt-out at the website.
The authors declare that they have no competing interests.
Patient characteristics.
Characteristics | Group A (n=12) | Group B (n=17) | P-value |
---|---|---|---|
Median age, years (range) | 69 (58-75) | 68 (48-74) | 0.444 |
Sex | 0.403 | ||
Male | 8(67) | 14(82) | |
Female | 4(33) | 3(18) | |
Performance status | 1.000 | ||
0 | 10(83) | 13(76) | |
1 | 2(17) | 4(24) | |
Creatinine clearance, ml/min | 0.369 | ||
≥60 | 8(67) | 10(59) | |
50-60 | 4(33) | 3(17) | |
40-50 | 0 | 3(17) | |
<40 | 0 | 1(6) | |
Histopathology | 0.414 | ||
Squamous cell carcinoma | 11(92) | 17(100) | |
Adenocarcinoma | 1(8) | 0 | |
Primary tumor location | 0.588 | ||
Upper | 6(50) | 6(35) | |
Middle | 4(33) | 9(53) | |
Lower | 2(17) | 2(12) | |
T stage | 0.311 | ||
T2 | 1(8) | 0 | |
T3 | 11(92) | 15(89) | |
T4 | 0 | 2(12) | |
N stage | 0.177 | ||
N0 | 0 | 4(24) | |
N1 | 6(50) | 5(29) | |
N2 | 5(42) | 8(47) | |
N3 | 1(8) | 0 | |
Clinical stage | 0.098 | ||
Ⅱ | 0 | 3(18) | |
Ⅲ | 10(83) | 14(82) | |
Ⅳ | 2(17) | 0 |
Data are presented as n (%), unless otherwise specified. P<0.05 was considered to indicate statistical significance.
Adverse events.
Adverse events | Any grade | Grade≥3 |
---|---|---|
Group A | ||
Leukopenia | 11(92) | 7(58) |
Neutropenia | 11(92) | 6(50) |
Anemia | 12(100) | 2(17) |
Thrombocytopenia | 8(67) | 1(8) |
Hypoalbuminemia | 12(100) | 1(8) |
Hyponatremia | 10(83) | 1(8) |
Hyperkalemia | 5(42) | 0 |
Hypokalemia | 4(33) | 1(8) |
Creatinine increased | 5(42) | 0 |
Elevated aspartate aminotransferase | 5(42) | 1(8) |
Anorexia | 2(17) | 1(8) |
Nausea | 4(33) | 0 |
Diarrhea | 4(33) | 1(8) |
Lung infection | 3(25) | 2(17) |
Hematemesis | 1(8) | 0 |
Group B | ||
Leukopenia | 10(59) | 1(6) |
Neutropenia | 10(59) | 1(6) |
Anemia | 17(100) | 2(12) |
Thrombocytopenia | 7(41) | 0 |
Hypoalbuminemia | 17(100) | 0 |
Hyponatremia | 14(82) | 0 |
Hyperkalemia | 11(65) | 0 |
Creatinine increased | 9(53) | 0 |
Elevated aspartate aminotransferase | 7(41) | 0 |
Elevated alanine aminotransferase | 8(47) | 0 |
Anorexia | 6(35) | 2(12) |
Nausea | 8(47) | 0 |
Fatigue | 10(59) | 0 |
Edema | 2(12) | 1(6) |
Data are presented as n (%).
Postoperative complications.
Postoperative complications | Number (%) |
---|---|
Group A (n=11) | |
Pleural effusion | 1(9) |
Lung infection | 4(36) |
Mediastinal infection | 1(9) |
Dyspnea | 1(9) |
Dysphagia | 1(9) |
Postoperative hemorrhage | 1(9) |
Wound infection | 1(9) |
Gastric fistula | 1(9) |
Group B (n=16) | |
Pleural effusion | 2(13) |
Lung infection | 5(31) |
Dyspnea | 2(13) |
Pneumothorax | 1(6) |
Atelectasis | 1(6) |
Dysphagia | 1(6) |
Anastomotic leakage | 2(13) |
Wound infection | 1(6) |
The total number of complications does not equal the number of patients because some patients had no complications.