Capecitabine or XELOX Does Not Significantly Improve Efficacy vs PF in Inoperable ESCC

Capecitabine (Xeloda) with or without oxaliplatin (XELOX) failed to improve the 2-year overall survival (OS) rate vs cisplatin plus fluorouracil (PF) as definitive concurrent chemoradiotherapy (DCRT) in patients with inoperable, locally advanced esophageal squamous cell carcinoma (ESCC), according to findings from the 3-arm, phase 3 CRTCOESC trial (NCT02025036) that were published in the Journal of Clinical Oncology.^1,2

With a median follow-up of 33.6 months (IQR, 18.0-46.8) the results indicated that the 2-year OS rate was 75.0%, 66.7%, and 70.9% in the capecitabine (n = 80), XELOX (n = 85), and PF (n = 81) arms, respectively. The hazard ratio (HR) for capecitabine vs PF was 0.91 (95% CI, 0.61-1.35; nominal P =.637); for XELOX vs PF, the HR was 0.86 (95% CI, 0.58-1.27; P =.444). The median OS was 40.9 months (95% CI, 34.4-49.9), 41.9 months (95% CI, 28.6-52.1), and 35.4 months (95% CI, 30.4-45.4), respectively.

The median progression-free survival (PFS) was 26.1 months (95% CI, 18.4-31.8), 30.2 months (95% CI, 15.9-39.6), and 28.2 months (95% CI, 16.6-34.9), respectively. The HR for capecitabine vs PF was 1.15 (95% CI, 0.79-1.68; nominal P = .450); for XELOX vs PF, the HR was 0.91 (95% CI, 0.62-1.33; nominal P = .615). The 2-year PFS rates were 52.8% (95% CI, 41.2%-63.1%), 56.5% (95% CI, 45.3%-66.2%), and 54.9% (95% CI, 43.2%-65.2%), respectively.

“Not surprisingly, single-agent fluoropyrimidine therapy was more favorably tolerated over combination chemotherapy, and for select patients, single-agent capecitabine may represent an alternative to combination chemotherapy in locally advanced inoperable squamous cell carcinoma of the esophagus,” JCO Associate Editor and gastrointestinal oncology Eileen M. O’Reilly, MD, of Memorial Sloan Kettering Cancer Center in New York, New York, and colleagues, wrote regarding the relevance of the study. “Limitations include [a] relatively small sample size and lack of [a] noninferiority design, and the application of these results to a global population are unclear.”

DCRT is standard of care for patients with locally advanced esophageal cancer who are not fit for or unwilling to undergo surgery, with several chemotherapy regimens recommended by the National Comprehensive Cancer Network and European Society for Medical Oncology, including paclitaxel and carboplatin, fluorouracil and oxaliplatin, and PF. However, because of comparable efficacy and reduced toxicity, paclitaxel plus carboplatin and fluorouracil plus oxaliplatin remain the preferred regimens despite efforts to improve outcomes with DCRT.

To evaluate a potentially better tolerated regimen and determine the value of adding consolidation chemotherapy to DCRT, investigators launched the CRTCOESC trial.

To be eligible for enrollment, patients between the ages of 18 and 75 needed to have pathologically confirmed ESCC with a clinical stage of cT1bN1-2M0 or T2-T4aN0-2M0 per the 7th edition of the American Joint Committee on Cancer Staging Manual. Additional requirements included an ECOG performance status of 0 to 2, pulmonary ventilation function above 80% of the predicted normal values, and adequate hematologic function.

Patients were randomly assigned 1:1:1 to 1 of 3 arms: capecitabine 625 mg/m² twice daily on days 1 through 5, 8 through 12, and 15 through 19 every 3 weeks for two cycles; intravenous oxaliplatin 65 mg/m² once daily on days 1 and 8, plus capecitabine 625 mg/m² twice daily on days 1 through 5, 8 through 12, and 15 through 19 every 3 weeks for two cycles (XELOX); or IV cisplatin 75 mg/m² once daily on day 1, plus IV fluorouracil 750 mg/m² once daily on days 1 through 4 every 4 weeks for two cycles (PF). Intensity-modulated radiotherapy was administered concurrently in 50 Gy/25 fractions.

For the consolidation portion, patients were again randomly assigned 1:1 to receive 2 cycles of the chemotherapy they had been assigned to initially as consolidation therapy (n = 121; capecitabine, n = 38; XELOX, n = 44; PF, n = 39) or nothing (n = 125; capecitabine, n = 42; XELOX, n = 41; PF, n = 42).

At week 16, patients underwent esophagogastroduodenoscopy (EGD), upper GI contrasts, and computed tomography scans of the cervical, thoracic, and abdominal regions. Clinical complete response (CR) was defined as the absence of residual disease in the esophagus and/or locoregional lymph nodes assessed by imaging, EGD, and biopsy. Follow-up continued every 3 months for up to 5 years with CT scans until disease progression, death, or consent withdrawal.

The primary end points were the 2-year OS rate and the incidence of grade 3 or greater AEs. Secondary end points included PFS and clinical CR. Exploratory end points were OS, PFS, and AEs in the non-consolidation and consolidation chemotherapy groups. Efficacy was analyzed in the intention-to-treat population, and safety was evaluated in patients who received one or more cycles of chemotherapy.

Additional results demonstrated that the clinical CR rate was 35% (n = 28) in the capecitabine arm, 37.6% (n = 32) in the XELOX arm, and 33.3% (n = 27) in the PF arm.

Moreover, the addition of consolidation chemotherapy led to an improvement in median OS vs DCRT alone, at 41.9 months (95% CI, 34.6-52.8) vs 36.9 months (95% CI, 28.5-44.0), respectively (HR, 0.71; 95% CI, 0.52-0.99; nominal P = .0403). The 2-year OS rates were 75.6% and 66.3%, respectively. The median PFS was 30.7 months (95% CI, 20.6-37.4) with consolidation and 24.9 months (95% CI, 16.6-32.2) without consolidation (HR, 0.857; 95% CI, 0.631-1.164; nominal P = .322). The 2-year PFS rates were 56.9% vs 52.7%, respectively.

Investigators further evaluated outcomes with and without consolidation according to treatment arm. In the capecitabine arm, the median OS was 44.2 months (95% CI, 34.4-61.9) with consolidation vs 36.9 months (95% CI, 24.9-46.8) without (HR, 0.71; 95% CI, 0.40-1.24; nominal P = .225); the median PFS was 26.5 months (95% CI, 16.3-35.8) vs 23.2 months (95% CI, 10.7-32.8), respectively (HR, 1.05; 95% CI, 0.63-1.74; nominal P = .860).

In the XELOX arm, the median OS was 41.6 months (95% CI, 25.6-65.8) with consolidation vs 42.3 months (95% CI, 23.1-62.4) without (HR, 0.96; 95% CI, 0.55-1.66; nominal P = .879); the median PFS was 29.5 months (95% CI, 14.8-50.4) vs 30.2 months (95% CI, 11.4-41.7), respectively (HR, 0.94; 95% CI, 0.55-1.61; nominal P = .832).

In the PF arm, the median OS was 44 months (95% CI, 32.4-not evaluable [NE]) with consolidation vs 30.4 months (95% CI, 23.3-37.8) without (HR, 0.50; 95% CI, 0.28-0.90; nominal P = .0193; the median PFS was 31.3 months (95% CI, 17.6-NE) vs 21.5 months (95% CI, 12.7-34.6), respectively (HR, 0.61; 95% CI, 0.35-1.08; nominal P = .0864).

During the study period, the median relative dose intensity (RDI) for capecitabine was 100% in the capecitabine arm, 100% for capecitabine and oxaliplatin in the XELOX arm, and 88.89% and 98.25% for fluorouracil and cisplatin in the PF arm, respectively.

Regarding safety, grade 3 or greater adverse effects (AEs) occurred in 28.8% (n = 23) of patients in the capecitabine arm, 36.5% (n = 31) in the XELOX arm, and 45.7% (n = 37) in the PF arm during the study period (capecitabine vs PF, nominal P = .034; capecitabine vs XELOX, nominal P = .332; XELOX vs PF, nominal P = .270). Moreover, the incidence of grade 3 or greater AEs was 23.8%, 31.8%, and 39.5% in the capecitabine, XELOX, and PF arms during the chemoradiotherapy phase; the respective rates during consolidation were 18.4%, 14.0%, and 24.3%, respectively. During the study period, the incidence of grade 3 or greater AEs was 35.6% with consolidation vs 38.3% without (nominal P = .693). Notably no AE-related deaths occurred.

“In conclusion, this study showed that capecitabine alone orXELOX 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,” the study authors concluded. “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.”

References

1. Jia R, Shan T, Zheng A, et al. 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. J Clin Oncol. Published online May 6, 2024. doi:10.1200/JCO.23.02009
2. Chemoradiotherapy of capecitabine with or without oxaliplatin versus cisplatin-5-FU for esophageal squamous cancer (CRTCOESC). ClinicalTrials.gov. Updated February 8, 2023. https://clinicaltrials.gov/study/NCT02025036