Abstract
PURPOSE
This phase 3 trial aimed to compare the efficacy and safety of capecitabine or capecitabine plus oxaliplatin (XELOX) with those of fluorouracil plus cisplatin (PF) in definitive concurrent chemoradiotherapy (DCRT) for inoperable locally advanced esophageal squamous cell carcinoma (ESCC).
METHODS
Patients were randomly assigned to receive two cycles of capecitabine, XELOX, or PF along with concurrent intensity-modulated radiation therapy. Patients in each arm were again randomly assigned to receive two cycles of consolidation chemotherapy or not. The primary end points were 2-year overall survival (OS) rate and incidence of grade ≥3 adverse events (AEs).
RESULTS
A total of 246 patients were randomly assigned into the capecitabine (n = 80), XELOX (n = 85), and PF (n = 81) arms. In capecitabine, XELOX, and PF arms, the 2-year OS rate was 75%, 66.7%, and 70.9% (capecitabine v PF: hazard ratio [HR], 0.91 [95% CI, 0.61 to 1.35]; nominal P = .637; XELOX v PF: 0.86 [95% CI, 0.58 to 1.27]; P = .444); the median OS was 40.9 (95% CI, 34.4 to 49.9), 41.9 (95% CI, 28.6 to 52.1), and 35.4 (95% CI, 30.4 to 45.4) months. The incidence of grade ≥3 AEs during the entire treatment was 28.8%, 36.5%, and 45.7%, respectively. Comparing the consolidation chemotherapy with the nonconsolidation chemotherapy groups, the median OS was 41.9 (95% CI, 34.6 to 52.8) versus 36.9 (95% CI, 28.5 to 44) months (HR, 0.71 [95% CI, 0.52 to 0.99]; nominal P = .0403).
CONCLUSION
Capecitabine or XELOX did not significantly improve the 2-year OS rate over PF in DCRT for inoperable locally advanced ESCC. Capecitabine showed a lower incidence of grade ≥3 AEs than PF did.
INTRODUCTION
Definitive concurrent chemoradiotherapy (DCRT) has been recommended for patients with locally advanced esophageal cancer (EC) who are unsuitable for surgery or unwilling to undergo surgery. The National Comprehensive Cancer Network and the European Society for Medical Oncology recommend several chemotherapy regimens as standard options for DCRT, including paclitaxel plus carboplatin, fluorouracil plus oxaliplatin, and fluorouracil plus cisplatin (PF).1,2 The RTOG 85-01 trial and INT 0123 trial, which consisted of two cycles of PF combined with radiotherapy, followed by two cycles of chemotherapy, showed high toxicity and poor therapy compliance rate.3,4 Paclitaxel plus carboplatin and fluorouracil plus oxaliplatin demonstrated comparable efficacy and lower toxicity than PF.5-7 Therefore, National Comprehensive Cancer Network prefers paclitaxel plus carboplatin or fluorouracil plus oxaliplatin.1 Moreover, several studies tried to improve the clinical outcomes of DCRT by adding induction chemotherapy, adding the epidermal growth factor receptor antibody cetuximab, or increasing the radiation dose, but most studies did not surpass the efficacy of the standard treatment.8-11 The prognosis of these patients remains poor.
CONTEXT
Key Objective
Definitive concurrent chemoradiotherapy (DCRT) is the standard treatment for inoperable locally advanced esophageal squamous cell carcinoma. Considering the adverse events in DCRT and the unclear clinical benefits of consolidation chemotherapy, the phase 3 trial evaluated the efficacy and safety of capecitabine or capecitabine plus oxaliplatin (XELOX) compared with those of fluorouracil plus cisplatin (PF) in DCRT and assessed the impact of adding consolidation chemotherapy to DCRT.
Knowledge Generated
Capecitabine or XELOX showed comparable efficacy with PF, with capecitabine demonstrating better tolerability than PF. In addition, consolidation chemotherapy provided a survival benefit over DCRT alone.
Relevance (E.M. O'Reilly)
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Not surprisingly single agent fluoropyrimidine therapy was more favorably tolerated over combination chemotherapy and for select patient's single agent capecitabine may represent an alternative to combination chemotherapy in locally advanced inoperable squamous cell carcinoma of the esophagus. Limitations include relatively small sample size and lack of non-inferiority design and the application of these results to a global population are unclear.*
*Relevance section written by JCO Associate Editor Eileen M. O'Reilly, MD.
One of the main challenges of DCRT for patients with EC is to reduce the adverse effects of radiation and chemotherapy, which often affect treatment completion. Capecitabine is an oral prodrug of fluorouracil that can be converted to fluorouracil in tumor tissues. Although capecitabine can replace fluorouracil in DCRT, evidence of capecitabine-based DCRT is scarce. A phase 3 trial compared four chemotherapy regimens plus radiotherapy for untreated advanced EC: epirubicin and cisplatin with either fluorouracil or capecitabine, or epirubicin and oxaliplatin with either fluorouracil or capecitabine. This study showed that capecitabine and oxaliplatin (XELOX) were as effective as fluorouracil and cisplatin.12 However, this study mainly included patients with esophageal adenocarcinoma, which was the major pathologic type of EC in North American and European countries.13,14 It is unclear whether XELOX is an ideal partner of DCRT for esophageal squamous cell carcinoma (ESCC), which accounts for 95% of Chinese EC cases.14 Moreover, no trial has directly compared the efficacy of XELOX with that of PF in DCRT.
Single-agent chemotherapy such as fluorouracil, nedaplatin, and docetaxel was reported to be feasible and tolerable for DCRT in patients with EC who were unsuitable for cisplatin, had N1 disease, or were older.15-18 In a phase 3 study of older patients with EC, DCRT with single-agent S-1 showed a higher 2-year overall survival (OS) rate (53.2% v 35.8%) and similar incidences of most grade ≥3 adverse events (AEs) compared with radiotherapy alone.18 Although S-1 is an oral fluoropyrimidine derivative similar to capecitabine, the efficacy of single-agent capecitabine in DCRT for ESCC remains unclear. Another interesting question is whether consolidation chemotherapy improves survival after DCRT. Here, we report the efficacy and safety of capecitabine, XELOX, and PF in DCRT for patients with inoperable locally advanced ESCC and present the clinical results of patients with or without two cycles of consolidation chemotherapy after undergoing DCRT.
METHODS
Inclusion Criteria
Eligible patients were between age 18 and 75 years and had pathologically confirmed ESCC with a clinical stage of cT1bN1-2M0 or T2-T4aN0-2M0 (7th edition of the American Joint Committee on Cancer Staging Manual). They were not suitable for surgery because of medical reasons or patient choice. Patients had an Eastern Cooperative Oncology Group performance status of 0-2, pulmonary ventilation function >80% of the predicted normal values, and adequate hematologic function. All amendments, including the Protocol (online only), were approved by the institutional review board of each participating institution. All patients provided written informed consents.
Procedures
Eligible patients were randomly allocated in a 1:1:1 ratio to three arms: capecitabine (625 mg/m2, twice daily, days 1-5, 8-12, 15-19 every 3 weeks for two cycles), XELOX (oxaliplatin, 65 mg/m2, intravenously [IV], once daily, days 1 and 8, and capecitabine, 625 mg/m2, twice daily, days 1-5, 8-12, 15-19, every 3 weeks for two cycles), or PF (cisplatin, 75 mg/m2, IV, once daily, day 1, and fluorouracil, 750 mg/m2, IV, once daily, days 1-4, every 4 weeks for two cycles). SAS 9.3 (SAS Institute, Cary, NC) was used to generate a random permutation sequence and to produce random patient assignment numbers. For patients who could not take capecitabine tablets, capecitabine was split into smaller pills and administered. For patients who had oral feeding difficulty, a nasal nutrition tube was inserted ahead of the DCRT to ensure the intake of the drug and sufficient enteral nutrition. Intensity-modulated radiation therapy was delivered concurrently by 50 Gy/25 fractions.
The patients in each treatment arm were again randomly allocated in a 1:1 ratio to receive either two cycles of consolidation chemotherapy (consolidation chemotherapy group) or none (nonconsolidation chemotherapy group). The consolidation chemotherapy regimen was the same as that used during CRT. Treatment was discontinued after completing CRT for patients in the nonconsolidation chemotherapy group or CRT and consolidation therapy for patients in the consolidation chemotherapy group. At week 16, patients underwent esophagogastroduodenoscopy (EGD), upper GI contrasts (UGI), and computed tomography (CT) scans of the cervical, thoracic, and abdominal regions. Those who had no residual disease in the esophagus and/or locoregional lymph nodes assessed by imaging, EGD, and biopsy pathology were defined as achieving a clinical complete response. All patients were subsequently assessed every 3 months using CT scans until disease progression, death, or withdrawal of consent. For patients who achieved a clinical complete response, additional EGD and biopsy were performed. AEs were monitored and recorded during the CRT and consolidation chemotherapy phases. For patients who received consolidation chemotherapy, the CRT phase was from the first cycle of treatment to before the third cycle of treatment. For patients who did not receive consolidation chemotherapy, the CRT phase was from the first cycle of treatment up to 90 days after the last dose. The consolidation chemotherapy phase was from the third cycle of treatment up to 90 days after the last dose. Survival follow-up was conducted every 3 months for up to 5 years after random assignment.
Outcomes
The primary end points were 2-year OS rate (time from random assignment to death from any cause) and incidence of grade ≥3 AEs. The secondary end points were progression-free survival (PFS: time from random assignment to the first event of local failure, metastatic recurrence, progression, or death) and clinical complete response. The exploratory end points were OS, PFS, and AEs in the nonconsolidation and consolidation chemotherapy groups. Efficacy was analyzed in an intention-to-treat (ITT) population (patients who underwent random assignment), and safety was analyzed in patients who received at least one cycle of chemotherapy.
Statistical Analysis
This study was designed to test the superiority of the 2-year OS rate in the capecitabine or XELOX arm versus the PF arm. Statistical assumptions were made only for 2-year OS rate, and the overall type-I error was controlled for this end point using the group sequential method. On the basis of the results of the RTOG 85-01 study, the 2-year OS rates were assumed to be 36% in the PF arm and 56% in the capecitabine and XELOX arms. A total of 142 deaths (56 in the PF arm, 43 in the capecitabine arm, and 43 in the XELOX arm; 99 deaths for each pair of comparisons) were required to detect an absolute 20% improvement in the 2-year OS rate (corresponding hazard ratio [HR], 0.57) in the capecitabine arm and the XELOX arm versus the PF arm by 80% power at an overall two-sided significance level of 0.05. If the difference in the 2-year OS rate was statistically significant between the XELOX and PF arms, the difference in the 2-year OS rate between the capecitabine and PF arms was tested. Considering a 15% dropout rate, 246 patients (82 per arm) would need to be randomly assigned in a 1:1:1 ratio to the three arms within 3 years and a minimum of 2-year follow-up would be required after the last patient was randomly assigned.
The Kaplan-Meier method was used to estimate survival outcomes. The log-rank test was used to compare the survival outcomes between the capecitabine arm/XELOX arm and the PF arm and between the consolidation chemotherapy and nonconsolidation chemotherapy groups. The Cox proportional hazard model was used to estimate HRs and corresponding 95% CIs. Subgroup analysis was performed for the baseline characteristics of interest. Fisher's exact test was used to compare toxicities in patients who received at least one cycle of chemotherapy. AEs were graded and recorded per the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. All P values were obtained using two-sided tests. Data were analyzed using SAS 9.4 (SAS Institute, Cary, NC) and SPSS version 19.0 (IBM Corp, Armonk, NY).
RESULTS
In total, 297 patients were screened and 246 were randomly assigned into capecitabine (n = 80), XELOX (n = 85), and PF (n = 81) arms between October 2014 and April 2020. In the secondary random assignment for consolidation chemotherapy, 125 patients were assigned to the nonconsolidation chemotherapy group (42, 41, and 42 patients in the capecitabine, XELOX, and PF arms, respectively) and 121 patients were assigned to the consolidation chemotherapy group (38, 44, and 39 patients in the capecitabine, XELOX, and PF arms, respectively). A total of 38, 43, and 37 patients received consolidation therapy with capecitabine, XELOX, and PF after DCRT, respectively. All patients completed CRT, and 37, 43, and 35 patients completed consolidation therapy (Fig 1). The baseline characteristics of the patients were well balanced between the three arms (Table 1).
FIG 1.
Trial profile. aIndicates that one patient was assigned to the nonconsolidation chemotherapy group in the PF arm, but actually received consolidation therapy with PF. PF, fluorouracil plus cisplatin.
TABLE 1.
Baseline Characteristics of Patients Included in the Study
| Characteristic | Capecitabine (n = 80) | XELOX (n = 85) | PF (n = 81) |
|---|---|---|---|
| Sex, No. (%) | |||
| Male | 46 (57.5) | 52 (61.2) | 48 (59.3) |
| Female | 34 (42.5) | 33 (38.8) | 33 (40.7) |
| Age, years, median (IQR) | 66.5 (61-71) | 67 (62-71) | 65 (61-70) |
| ECOG performance status, No. (%) | |||
| 0 | 22 (27.5) | 21 (24.7) | 21 (25.9) |
| 1 | 52 (65) | 60 (70.6) | 54 (66.7) |
| 2 | 6 (7.5) | 4 (4.7) | 6 (7.4) |
| Stage (AJCC, 7th edition), No. (%) | |||
| IA | 1 (1.3) | 0 | 0 |
| IIA | 17 (21.3) | 25 (29.4) | 21 (25.9) |
| IIB | 7 (8.8) | 11 (12.9) | 10 (12.3) |
| IIIA | 10 (12.5) | 5 (5.9) | 4 (4.9) |
| IIIB | 41 (51.3) | 35 (41.2) | 35 (43.2) |
| IIIC | 4 (5) | 9 (10.6) | 11 (13.6) |
| N stage, No. (%) | |||
| N0 | 31 (38.8) | 43 (50.6) | 37 (45.7) |
| N1 | 40 (50) | 38 (44.7) | 33 (40.7) |
| N2 | 8 (10) | 4 (4.7) | 11 (13.6) |
| N3 | 1 (1.3) | 0 | 0 |
| Tumor location, No. (%) | |||
| Cervical | 6 (7.5) | 6 (7.1) | 4 (4.9) |
| Upper | 34 (42.5) | 24 (28.2) | 24 (29.6) |
| Middle | 33 (41.3) | 50 (58.8) | 43 (53.1) |
| Lower | 11 (13.8) | 10 (11.8) | 15 (18.5) |
| Multiple sites | 4 (5) | 5 (5.9) | 5 (6.2) |
| Pathologic grade, No. (%) | |||
| G1 | 8 (10) | 14 (16.5) | 10 (12.3) |
| G2 | 21 (26.3) | 12 (14.1) | 17 (21) |
| G3 | 14 (17.5) | 15 (17.6) | 9 (11.1) |
| Gx | 37 (46.3) | 44 (51.8) | 45 (55.6) |
| Smoking, No. (%) | |||
| Never | 49 (61.3) | 44 (51.8) | 47 (58) |
| Former or current | 31 (38.8) | 41 (48.2) | 34 (42) |
| Drinking, No. (%) | |||
| Never | 43 (53.8) | 43 (50.6) | 42 (51.9) |
| Former or current | 37 (46.3) | 42 (49.4) | 39 (48.1) |
Abbreviations: AJCC, American Joint Committee on Cancer; ECOG, Eastern Cooperative Oncology Group; PF regimen, fluorouracil plus cisplatin; XELOX regimen, capecitabine plus oxaliplatin.
As of June 27, 2023, the median follow-up time was 33.6 months (IQR, 18-46.8) in the ITT population. In the capecitabine, XELOX, and PF arms, the 2-year OS rate was 75%, 66.7%, and 70.9% (capecitabine v PF: HR, 0.91 [95% CI, 0.61 to 1.35]; nominal P = .637; XELOX v PF: HR, 0.86 [95% CI, 0.58 to 1.27]; P = .444); the median OS was 40.9 (95% CI, 34.4 to 49.9), 41.9 (95% CI, 28.6 to 52.1), and 35.4 (95% CI, 30.4 to 45.4) months, respectively. Capecitabine or XELOX did not significantly improve the 2-year OS rate over PF in DCRT for inoperable locally advanced ESCC. The median PFS was 26.1 (95% CI, 18.4 to 31.8), 30.2 (95% CI, 15.9 to 39.6), and 28.2 (95% CI, 16.6 to 34.9) months, respectively (capecitabine v PF: HR, 1.15 [95% CI, 0.79 to 1.68]; nominal P = .450; XELOX v PF: HR, 0.91 [95% CI, 0.62 to 1.33]; nominal P = .615; Figs 2A and 2B and Table 2).
FIG 2.
Survival outcomes. (A) Overall survival and (B) progression-free survival for the capecitabine, XELOX, and PF arms. (C) Overall survival and (D) progression-free survival for the nonconsolidation chemotherapy and consolidation chemotherapy groups. PF, fluorouracil plus cisplatin; XELOX, capecitabine plus oxaliplatin.
TABLE 2.
Summary of Survival Outcomes
| Survival Outcome | Capecitabine (n = 80) | XELOX (n = 85) | PF (n = 81) |
|---|---|---|---|
| Follow-up, median, months (IQR) | 35.3 (21.8-47.1) | 34.5 (18.6-52.1) | 31.1 (16.1-42.2) |
| Overall survival, median, months (95% CI) | 40.9 (34.4 to 49.9) | 41.9 (28.6 to 52.1) | 35.4 (30.4 to 45.4) |
| 2-year overall survival rate, % (95% CI) | 75 (64 to 83.1) | 66.7 (55.6 to 75.7) | 70.9 (59.5 to 79.6) |
| Hazard ratio (95% CI) | 0.91 (0.61 to 1.35)a | 0.86 (0.58 to 1.27)b | |
| P | .637a,c | .444b | |
| Progression-free survival, months, median (95% CI) | 26.1 (18.4 to 31.8) | 30.2 (15.9 to 39.6) | 28.2 (16.6 to 34.9) |
| 2-year progression-free survival rate, % (95% CI) | 52.8 (41.2 to 63.1) | 56.5 (45.3 to 66.2)b | 54.9 (43.2 to 65.2) |
| Hazard ratio (95% CI) | 1.15 (0.79 to 1.68)a | 0.91 (0.62 to 1.33)b | |
| P | .45a,c | .615b,c |
Abbreviations: PF regimen, fluorouracil plus cisplatin; XELOX regimen, capecitabine plus oxaliplatin.
Indicates a comparison between capecitabine and PF.
Indicates a comparison between XELOX and PF.
Indicates that the P value was nominal.
In addition, 28 of 80 (35%) patients in the capecitabine arm, 32 of 85 (37.6%) in the XELOX arm, and 27 of 81 (33.3%) in the PF arm achieved a clinical complete response. The median OS of 87 patients with a clinical complete response was higher than that of 159 patients without a clinical complete response (52.8 [95% CI, 44 to 62.1] v 32.3 [95% CI, 27.5 to 36.2] months; HR, 0.45 [95% CI, 0.31 to 0.64]; nominal P < .0001).
During the total therapy, the median relative dose intensity (RDI) of capecitabine was 100% in the capecitabine arm. In the XELOX arm, the median RDI was 100% for both capecitabine and oxaliplatin. In the PF arm, the median RDI of fluorouracil and cisplatin was 88.89% and 98.25%, respectively (Data Supplement, Table S1 [online only]). Grade ≥3 AEs occurred in 23 patients (28.8%) in the capecitabine arm, 31 (36.5%) in the XELOX arm, and 37 (45.7%) in the PF arm during the total therapy. It was lower in the capecitabine arm than in the PF arm (nominal P = .034); however, there were no differences between the capecitabine and XELOX arms (nominal P = .332) or between the XELOX and PF arms (nominal P = .270; Table 3 and Data Supplement, Table S2). Moreover, the incidence of grade ≥3 AEs was 23.8%, 31.8%, and 39.5% in the capecitabine, XELOX, and PF arms during the CRT phase and was 18.4%, 14%, and 24.3% in the respective arms during the consolidation chemotherapy phase (Data Supplement, Tables S3 and S4). No deaths occurred because of AEs.
TABLE 3.
Adverse Events in the Capecitabine, XELOX, and PF Arms During the Total Therapy
| Characteristic | Any Grade | Grade ≥3 | ||||
|---|---|---|---|---|---|---|
| Capecitabine (n = 80), No. (%) | XELOX (n = 85), No. (%) | PF (n = 81), No. (%) | Capecitabine (n = 80), No. (%) | XELOX (n = 85), No. (%) | PF (n = 81), No. (%) | |
| Any | 74 (92.5) | 85 (100) | 81 (100) | 23 (28.8) | 31 (36.5) | 37 (45.7) |
| GI | ||||||
| Nausea | 63 (78.8) | 72 (84.7) | 73 (90.1) | 3 (3.8) | 1 (1.2) | 4 (4.9) |
| Abdominal distension | 12 (15) | 22 (25.9) | 27 (33.3) | 1 (1.3) | 0 | 0 |
| Anorexia | 7 (8.8) | 13 (15.3) | 14 (17.3) | 0 | 1 (1.2) | 2 (2.5) |
| Diarrhea | 3 (3.8) | 6 (7.1) | 6 (7.4) | 0 | 1 (1.2) | 0 |
| Hematologic | ||||||
| Leukopenia | 44 (55) | 61 (71.8) | 64 (79) | 2 (2.5) | 6 (7.1) | 17 (21) |
| Anemia | 11 (13.8) | 12 (14.1) | 21 (25.9) | 0 | 1 (1.2) | 2 (2.5) |
| Thrombocytopenia | 9 (11.3) | 16 (18.8) | 19 (23.5) | 2 (2.5) | 4 (4.7) | 6 (7.4) |
| Bone marrow inhibition | 0 | 0 | 3 (3.7) | 0 | 0 | 2 (2.5) |
| Radiation induced | ||||||
| Esophageal pain | 36 (45) | 40 (47.1) | 27 (33.3) | 6 (7.5) | 2 (2.4) | 4 (4.9) |
| Esophagitis | 32 (40) | 26 (30.6) | 35 (43.2) | 2 (2.5) | 1 (1.2) | 1 (1.2) |
| Pneumonitis | 8 (10) | 4 (4.7) | 5 (6.2) | 6 (7.5) | 3 (3.5) | 5 (6.2) |
| Dermatitis | 1 (1.3) | 0 | 2 (2.5) | 0 | 0 | 1 (1.2) |
| Esophagotracheal fistula | 1 (1.3) | 3 (3.5) | 0 | 1 (1.3) | 3 (3.5) | 0 |
| Neurologic | ||||||
| Peripheral neuropathy | 6 (7.5) | 43 (50.6) | 35 (43.2) | 0 | 3 (3.5) | 1 (1.2) |
| Constitutional symptoms | ||||||
| Pneumonitis | 19 (23.8) | 26 (30.6) | 17 (21) | 12 (15) | 11 (12.9) | 12 (14.8) |
| Fever | 10 (12.5) | 13 (15.3) | 10 (12.3) | 0 | 1 (1.2) | 0 |
| Fatigue | 6 (7.5) | 5 (5.9) | 3 (3.7) | 0 | 0 | 0 |
| Skin and mucosa | ||||||
| Hand-foot syndrome | 20 (25) | 22 (25.9) | 4 (4.9) | 0 | 1 (1.2) | 0 |
| Mucositis | 7 (8.8) | 11 (12.9) | 26 (32.1) | 1 (1.3) | 2 (2.4) | 7 (8.6) |
Abbreviations: PF regimen, fluorouracil plus cisplatin; XELOX regimen, capecitabine plus oxaliplatin.
Between the consolidation chemotherapy group and nonconsolidation chemotherapy group, the median OS was 41.9 (95% CI, 34.6 to 52.8) and 36.9 (95% CI, 28.5 to 44) months (HR, 0.71 [95% CI, 0.52 to 0.99]; nominal P = .0403). The 2-year OS rate was 75.6% and 66.3%, respectively. The median PFS was 30.7 (95% CI, 20.6 to 37.4) and 24.9 (95% CI, 16.6 to 32.2) months (HR, 0.857 [95% CI, 0.631 to 1.164]; nominal P = .322), and the 2-year PFS rate was 56.9% and 52.7%, respectively (Figs 2C and 2D). Subgroup analysis was conducted according to the baseline characteristics. Among the three subgroups of patients with positive lymph nodes, stage III disease, and male sex, the consolidation chemotherapy group showed better OS than the nonconsolidation chemotherapy group (Data Supplement, Fig S1). During the total therapy, the incidence of grade ≥3 AEs was 38.3% and 35.6% (nominal P = .693) in the nonconsolidation chemotherapy and consolidation chemotherapy groups (Data Supplement, Table S5).
In the capecitabine arm, the median OS was 44.2 months (95% CI, 34.4 to 61.9) in the consolidation chemotherapy group and 36.9 months (95% CI, 24.9 to 46.8) in the nonconsolidation chemotherapy group (HR, 0.71 [95% CI, 0.40 to 1.24]; nominal P = .225); the median PFS was 26.5 (95% CI, 16.3 to 35.8) and 23.2 (95% CI, 10.7 to 32.8) months (HR, 1.05 [95% CI, 0.63 to 1.74]; nominal P = .860). In the XELOX arm, the median OS was 41.6 months (95% CI, 25.6 to 65.8) in the consolidation chemotherapy group and 42.3 months (95% CI, 23.1 to 62.4) in the nonconsolidation chemotherapy group (HR, 0.96 [95% CI, 0.55 to 1.66]; nominal P = .879); the median PFS was 29.5 (95% CI, 14.8 to 50.4) and 30.2 (95% CI, 11.4 to 41.7) months (HR, 0.94 [95% CI, 0.55 to 1.61]; nominal P = .832). In the PF arm, the median OS was 44 months (95% CI, 32.4 to not evaluable [NE]) in the consolidation chemotherapy group and 30.4 months (95% CI, 23.3 to 37.8) in the nonconsolidation chemotherapy group (HR, 0.50 [95% CI, 0.28 to 0.90]; nominal P = .0193); the median PFS was 31.3 (95% CI, 17.6 to NE) and 21.5 (95% CI, 12.7 to 34.6) months (HR, 0.61 [95% CI, 0.35 to 1.08]; nominal P = .0864; Data Supplement, Fig S2). The Data Supplement (Tables S6-S8) shows the AEs in patients who received capecitabine, XELOX, or PF in the nonconsolidation chemotherapy or the consolidation chemotherapy groups during the total therapy.
DISCUSSION
This study showed that DCRT with capecitabine or XELOX did not result in a superior 2-year OS rate compared with PF and the incidence of grade ≥3 AEs was lower in the capecitabine arm than in the PF arm. The similar 2-year OS rate and more tolerable toxicity profile of capecitabine compared with PF suggest its potential as an alternative option for patients with inoperable locally advanced ESCC.
This study showed that the 2-year OS rate was 75% in the capecitabine arm, 66.7% in the XELOX arm, and 70.9% in the PF arm. The RTOG 85-01 study administered patients with inoperable localized EC (88% of patients with ESCC) with PF combined with radiotherapy or radiotherapy alone and demonstrated a 2-year OS rate of 50% versus 38% in the two groups.3 The higher 2-year OS rate in this study may be attributed to the advances in radiotherapy techniques, comprehensive supportive care, and high treatment compliance. Before radiotherapy, 23 patients with esophageal stenosis and dysphagia underwent gastroscope-assisted nutrition tube placement to maintain good nutritional status throughout the treatment. In addition, the 2-year OS rate in this study was similar to that in the ESO-Shanghai 1 study comparing paclitaxel plus fluorouracil (TF) and PF (60.6% v 61.5%) and the study by Xu et al comparing 60 and 50 Gy combined with docetaxel and cisplatin (DC, 65.1% v 62.8%).11,19
Although the RTOG 85-01 study used two cycles of chemotherapy combined with radiotherapy followed by two cycles of consolidation chemotherapy,3 direct evidence comparing the efficacy with or without consolidation chemotherapy is still lacking. In this study, the median OS was lower for the capecitabine, XELOX, and PF (40.9, 41.9, and 35.4 months, respectively) compared with the ESO-Shanghai 1 study (47.6 and 40.3 months for TF and PF) and the study by Xu et al (45.3 and 41.2 months for 60 and 50 Gy combined with DC).11,19 This may be because only half of the patients in this study received consolidation chemotherapy. Indeed, in this study, patients who received consolidation chemotherapy had a higher median OS (41.9 v 36.9 months) and similar incidence of grade ≥3 AEs compared with those who did not. Intriguingly, the longer duration of chemotherapy in the consolidation chemotherapy group did not increase the incidence of grade ≥3 AEs. This discrepancy may be largely explained by the fact that most patients who had AEs during the DCRT phase experienced similar AEs during the consolidation chemotherapy phase without an increase in severity. Therefore, these AEs were not counted as new events in the consolidation chemotherapy group. Subgroup analysis suggested that consolidation chemotherapy may benefit patients with positive lymph nodes, stage III disease, and male sex. However, this was not conclusive owing to the small sample size.
Considering the AEs associated with radiation, this study enrolled patients with pulmonary ventilation function above 80% of normal, limited lung volume receiving over 5 Gy to <50%, and performed chest CT and upper GI barium tests after 40 Gy/20 fractions of radiotherapy. In this study, the highest grade of radiation-induced esophagitis and pneumonia was 4. However, the ESO-Shanghai 1 study reported that two and three patients developed grade 5 esophagitis and pneumonia, respectively.19 In the study by Xu et al, the 60 and 50 Gy groups had five and two patients who developed grade 5 esophagitis and pneumonia, respectively.11
Positron emission tomography (PET)-CT has higher sensitivity than CT for the staging of metastatic disease and for the evaluation of distant lymphatic and hematogenous metastases in patients with ESCC after CRT.1 However, this study enrolled patients in 2014, when the standard staging of patients was based on CT rather than PET-CT. In addition, treatment response in this study was evaluated using EGD, UGI, and CT, which may differ from the current practice. Therefore, differences in staging and treatment response assessment methods may affect the results of this study. Furthermore, this study used the XELOX regimen, in which oxaliplatin was administered at a dose of 65 mg/m2 once daily on days 1 and 8, every 3 weeks. However, the use of oxaliplatin is uncommon. Nevertheless, this regimen was similar to that used in a randomized phase 2 study of XELOX or irinotecan in patients with colorectal cancer published in 2010.20 We previously conducted a study of combined oxaliplatin and S-1 in patients with advanced gastric cardiac adenocarcinoma and used the same dose and schedule of oxaliplatin, which gave us some experience with oxaliplatin.21 Caution is needed when interpreting XELOX results. In particular, consolidation chemotherapy did not improve OS compared with nonconsolidation chemotherapy in the XELOX arm but improved OS in the PF and capecitabine arms.
This study has some limitations. We overestimated the benefit of capecitabine or XELOX over PF, and we did not adopt a noninferiority design to compare these regimens. Although this was a phase 3 trial, the relatively small sample size required validation in a larger population. Furthermore, this study included Chinese patients with ESCC who had different characteristics from non-Asian patients with ESCC. For example, 57% of the patients in this study had never smoked, whereas most Western patients with ESCC were smokers or had a history of smoking.22,23 Therefore, the generalizability of the findings of this study to other regions may be limited.
In conclusion, this study showed that capecitabine alone or XELOX did not improve efficacy but was comparable with PF in DCRT. However, capecitabine showed better tolerability than PF did. Therefore, capecitabine alone may be considered as an alternative to the PF in DCRT. Furthermore, consolidation chemotherapy may provide a survival benefit over DCRT alone. These findings might have potential implications for the management of inoperable locally advanced ESCC and for guiding treatment choices.
ACKNOWLEDGMENT
We are grateful to all patients, their families, and the site investigators who participated in the study. We would like to express our gratitude to Wending Sun for her contributions to writing and to Xingwang Wang for his contribution to the revisions of the manuscript (both employed by Jiangsu Hengrui Pharmaceuticals).
Dan Zhou
Employment: BioNTech SE
Stock and Other Ownership Interests: BioNTech SE
Research Funding: BioNTech SE
No other potential conflicts of interest were reported.
PRIOR PRESENTATION
Presented in part at the ASCO 2017 Annual Meeting, Chicago, IL, June 2-6, 2017; the ASCO 2020 Virtual Annual Meeting, Chicago, IL, May 29-June 2, 2020; and ASCO GI 2022, San Francisco, CA, January 20-22, 2022.
SUPPORT
Supported by the Henan Province Medical Science and Technology Research Project (LHGJ20220683), Luoyang City Science and Technology Development Plan (2302015Y), and Jiangsu Hengrui Pharmaceuticals Co, Ltd.
CLINICAL TRIAL INFORMATION
R.J., T.S., and A.Z. contributed equally to this work as joint first authors. L.W., F.Z., and S.G. contributed equally to this work as joint senior authors.
DATA SHARING STATEMENT
The data support the findings of this study are available from the corresponding author upon reasonable request.
AUTHOR CONTRIBUTIONS
Conception and design: Ruinuo Jia, Tanyou Shan, Dan Zhou, Shegan Gao
Administrative support: Ruinuo Jia, Lixin Wan, Fuyou Zhou
Provision of study materials or patients: Ruinuo Jia, Yaowen Zhang, Yingjuan Zheng, Zhiwei Chang, Qiming Wang, Lixin Wan, Fuyou Zhou
Collection and assembly of data: Ruinuo Jia, Tanyou Shan, Anping Zheng, Yaowen Zhang, Ping Lu, Guifang Zhang, Feng Wang, Zhiqiao Xu, Guobao Zheng, Dongxia Tang, Weiguo Zhang, Wanying Li, Ruonan Li, Yibo Guo, Lina Liu, Xiaoyong Luo, Yingjuan Zheng, Zhiwei Chang, Qiming Wang, Xinshuai Wang, Xiaozhi Yuan, Guoqiang Kong, Shuoguo Li, Ruina Yang, Jing Ren, Weijiao Yin, Jingxia Li, Junqian Zhang, Ziqi Wang, Manxi Sheng, Bingyi Xu, Liuyan Li, Xiaoyi Liu, Shegan Gao
Data analysis and interpretation: Ruinuo Jia, Ruonan Li, Zhiwei Chang, Qiming Wang, Zhihao Lu, Lixin Wan, Fuyou Zhou, Shegan Gao
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Capecitabine or Capecitabine Plus Oxaliplatin Versus Fluorouracil Plus Cisplatin in Definitive Concurrent Chemoradiotherapy for Locally Advanced Esophageal Squamous Cell Carcinoma (CRTCOESC): A Multicenter, Randomized, Open-Label, Phase 3 Trial
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.
Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).
Dan Zhou
Employment: BioNTech SE
Stock and Other Ownership Interests: BioNTech SE
Research Funding: BioNTech SE
No other potential conflicts of interest were reported.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data support the findings of this study are available from the corresponding author upon reasonable request.