Author: Charles Bankhead, Staff Writer, MedPage Today
The addition of a targeted agent to definitive chemoradiation failed to improve survival in an unselected population with esophageal cancer, a randomized trial showed. In fact, patients who received cetuximab (Erbitux) with chemoradiation had significantly worse overall survival (OS) reflected in a 50% increase in the hazard versus chemoradiation alone, reported Thomas Crosby, MD, of Velindre Hospital in Cardiff, Wales, and colleagues.
Investigators could not find any subgroup of patients who benefited from cetuximab, they said in a presentation at the Gastrointestinal Cancers Symposium.
“The addition of cetuximab cannot be recommended to standard definitive chemoradiotherapy in the treatment of unselected patients with esophageal cancer,” Crosby said.
“The use of high-quality definitive chemoradiotherapy in the treatment of localized, poor-prognosis esophageal cancer was associated with excellent survival compared with previous radiotherapy and surgical series,” he added.
Randomized trials have shown that definitive (or primary) chemoradiation improves survival in localized esophageal cancer compared with a single treatment modality. In England, definitive chemoradiation has been used primarily for patients with localized disease that is unsuitable for surgery, Crosby said.
Add-on therapy with cetuximab has improved outcomes in other cancers, notably head and neck cancer and colorectal cancer. The findings provided a rationale for evaluating the addition of cetuximab to primary radiation therapy for localized esophageal cancer.
Crosby presented results of a randomized trial wherein patients with localized (stage I-III) esophageal cancer (less than 10 cm). Patients were excluded if they had celiac lymph-node involvement.
The patients received cisplatin-capecitabine (Xeloda) chemotherapy with or without cetuximab. After 6 weeks of chemotherapy, patients underwent definitive conformal radiation therapy at a total dose of 50 Gy in 25 fractions.
The trial had two stages. The first stage had a primary endpoint of treatment failure-free survival (TFFS), defined as alive at 6 months with no residual cancer in biopsy specimens and no evidence of disease progression outside the radiation therapy field. Secondary endpoints were toxicity, quality of life, overall survival (OS), and feasibility of recruitment. The first stage of the trial had an accrual target of 180 patients.
The trial’s second stage had a primary endpoint of OS and accrual to 420 patients.
However, the trial never reached second stage, but ended after a planned stage one analysis convinced the independent review committee that continued accrual to meet the primary endpoint would be futile.
Treatment and follow-up continued with enrolled patients, and the final analysis included 258 patients who had completed the 6-month assessment of disease status.
Crosby reported that patients randomized to conventional chemoradiation without cetuximab had a TFFS of 77% whereas the cetuximab group had a TFFS of 66%. All survival outcomes favored omission of cetuximab:
Median OS: 25.4 months versus 22.1 months
2-year survival: 56% versus 43.1%
Median progression-free survival: 19.4 months versus 15.9 months
The analysis showed a marked difference in median OS between patients who met the TFFS goal at 6 months and those who did not: 26.7 months versus 8.3 months.
Comparison of OS in the two arms yielded hazard ratio of 1.53 for the cetuximab arm versus chemoradiation only (P=0.035).
In addition to the inferior outcomes with cetuximab, addition of the targeted agent added to the toxicity burden. The cetuximab arm had an 81.4% incidence of grade 3 to 5 toxicity compared with 72.9% without cetuximab.
Patients who received cetuximab in addition to chemoradiation had significantly more grade 3 to 5 dermatologic toxicity (21.7% versus 3.9%, P<0.001) and metabolic/biochemical toxicity (24.0% versus 10.9%, P=0.005).
Additionally, the analysis revealed a trend toward more cardiac adverse events in the cetuximab arm (6.2% versus 1.6%, P=0.053).
The addition of cetuximab also adversely affected adherence to the treatment protocol. Patients in the cetuximab arm were significantly less likely to receive full doses of cisplatin (76.7% versus 89.9%, P=0.005), capecitabine (69.0% versus 85.3%, P=0.002), and radiation therapy (75.2% versus 86.0%, P=0.027).
Additionally, almost a third of patients did not receive the prescribed dose of cetuximab.
“Future strategies to improve the outcome of definitive chemoradiotherapy in esophageal cancer must focus on developing evidence-based biomarkers to select treatments and incorporating newer radiotherapy technologies and targeted systemic treatment to safely intensify treatment, including a higher radiotherapy dose,” Crosby said.