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ECX chemotherapy shows some benefit without OS improvement in advanced esophageal cancer

CHICAGO — A chemotherapy regimen composed of epirubicin, cisplatin and capecitabine demonstrated higher overall toxicity without improving OS compared with cisplatin and 5 fluorouracil in patients with surgically treated esophageal cancer, according to the results of a phase 3 trial presented at the ASCO Annual Meeting.

However, the treatment regimen resulted in some benefit in PFS, DFS and tumor regression at resection, results showed.

A neoadjuvant chemotherapy regimen composed of two cycles of cisplatin and 5 fluorouracil followed by surgery serves as the standard of care for locally advanced esophageal cancer, according to study background.

“In the OEO2 trial [Allum WH, et al. J Clin Oncol. 2009;doi:10.1200/JCO.2009.22.2083], two cycles of cisplatin and 5 fluorouracil increased 2-year survival rates from 34% to 43%,” David Cunningham, MD, FRCP, head of the gastrointestinal unit at The Royal Marsden Hospital in Surrey, U.K., said during a presentation. “The MAGIC trial [Cunningham D, et al. N Engl J Med. 2006:doi:10.1056/NEJMoa055531.] showed that epirubicin, cisplatin and capecitabine improved survival from 23% to 36%. This particular study was designed to increase the intensity and number of cycles of chemotherapy prior to surgery.”

Cunningham and colleagues evaluated data from 897 patients (median age, 62 years; interquartile range [IQR], 56-67; 90% male) with lower esophageal and junctional adenocarcinoma. The researchers randomly assigned patients to receive the standard chemotherapy regimen (n = 451) or four cycles of epirubicin, cisplatin and capecitabine (ECX; n = 446) followed by esophagectomy with 2-field lymphadenectomy.

OS served as the primary endpoint. PFS, DFS, pathological R0 resection rate, Mandard grade and quality of life served as secondary endpoints.

Ninety-six percent of patients assigned cisplatin and 5 fluorouracil received two treatment cycles and 89% of patients assigned ECX received more than three cycles.

Overall, 315 deaths occurred among patients who received the standard chemotherapy regimen and 298 deaths occurred among patients assigned ECX. The trial combination did not exhibit statistically significant superiority to the standard chemotherapy regimen (HR = 0.92; 95% CI, 0.79-1.08).

Similar 3-year survival rates occurred among patients assigned the trial combination and the standard chemotherapy regimen (42% vs. 39%).

Comparable rates of post-operative complications occurred on the standard chemotherapy and ECX arms (57% vs. 62%). Researchers also observed similarly low rates of death at 30 days (2% for both) and 90 days (4% vs. 5%) following surgery.

However, researchers observed slightly improved PFS (HR = 0.86; 95% CI, 0.74-1.01) and DFS (HR = 0.88; 95% CI, 0.75-1.03) among patients who received ECX.

“At the present time, 115 patient who received [the standard chemotherapy regimen] and 136 patients who received ECX are currently alive and progression-free,” Cunningham said.

“Although not statistically significant, clearly the HR is in favor [of ECX].”

More patients assigned ECX than standard chemotherapy achieved R0 resection rates (66% vs. 60%), a Mandard grade of 3 or lower (32% vs. 15%) and complete response (11% vs. 3%).

Younger patients (aged ≤ 70 years) and patients with node-negative disease exhibited greater benefit from ECX compared with the standard chemotherapy regimen, Cunningham said.

Researchers observed a significantly lower incidence of grade 3 or 4 adverse events among patients who received the standard chemotherapy regimen (30% vs. 47%; P < .001).

“The survival in both arms of this trial were better than expected,” Cunningham said. “This is encouraging for patients with esophageal gastric cancer. We are also seeing a trend towards improvement with ECX with regard to tumor regression rates — which were significantly better — and a PFS that was not quite significantly better. This did not, however, translate into a survival advantage.” – by Cameron Kelsall

Reference:

Alderson D, et al. Abstract 4002. Presented at: ASCO Annual Meeting; May 29-June 2, 2015; Chicago.

Disclosure: Cunningham reports receiving research funding from Amgen, AstraZeneca, Celgene, MedImmune, Merck Serono, Merrimack and Sanofi. Please see the abstract for a list of all other researchers’ relevant financial disclosures.

CHICAGO — A chemotherapy regimen composed of epirubicin, cisplatin and capecitabine demonstrated higher overall toxicity without improving OS compared with cisplatin and 5 fluorouracil in patients with surgically treated esophageal cancer, according to the results of a phase 3 trial presented at the ASCO Annual Meeting.

However, the treatment regimen resulted in some benefit in PFS, DFS and tumor regression at resection, results showed.

A neoadjuvant chemotherapy regimen composed of two cycles of cisplatin and 5 fluorouracil followed by surgery serves as the standard of care for locally advanced esophageal cancer, according to study background.

“In the OEO2 trial [Allum WH, et al. J Clin Oncol. 2009;doi:10.1200/JCO.2009.22.2083], two cycles of cisplatin and 5 fluorouracil increased 2-year survival rates from 34% to 43%,” David Cunningham, MD, FRCP, head of the gastrointestinal unit at The Royal Marsden Hospital in Surrey, U.K., said during a presentation. “The MAGIC trial [Cunningham D, et al. N Engl J Med. 2006:doi:10.1056/NEJMoa055531.] showed that epirubicin, cisplatin and capecitabine improved survival from 23% to 36%. This particular study was designed to increase the intensity and number of cycles of chemotherapy prior to surgery.”

Cunningham and colleagues evaluated data from 897 patients (median age, 62 years; interquartile range [IQR], 56-67; 90% male) with lower esophageal and junctional adenocarcinoma. The researchers randomly assigned patients to receive the standard chemotherapy regimen (n = 451) or four cycles of epirubicin, cisplatin and capecitabine (ECX; n = 446) followed by esophagectomy with 2-field lymphadenectomy.

OS served as the primary endpoint. PFS, DFS, pathological R0 resection rate, Mandard grade and quality of life served as secondary endpoints.

Ninety-six percent of patients assigned cisplatin and 5 fluorouracil received two treatment cycles and 89% of patients assigned ECX received more than three cycles.

Overall, 315 deaths occurred among patients who received the standard chemotherapy regimen and 298 deaths occurred among patients assigned ECX. The trial combination did not exhibit statistically significant superiority to the standard chemotherapy regimen (HR = 0.92; 95% CI, 0.79-1.08).

Similar 3-year survival rates occurred among patients assigned the trial combination and the standard chemotherapy regimen (42% vs. 39%).

Comparable rates of post-operative complications occurred on the standard chemotherapy and ECX arms (57% vs. 62%). Researchers also observed similarly low rates of death at 30 days (2% for both) and 90 days (4% vs. 5%) following surgery.

However, researchers observed slightly improved PFS (HR = 0.86; 95% CI, 0.74-1.01) and DFS (HR = 0.88; 95% CI, 0.75-1.03) among patients who received ECX.

“At the present time, 115 patient who received [the standard chemotherapy regimen] and 136 patients who received ECX are currently alive and progression-free,” Cunningham said.

“Although not statistically significant, clearly the HR is in favor [of ECX].”

More patients assigned ECX than standard chemotherapy achieved R0 resection rates (66% vs. 60%), a Mandard grade of 3 or lower (32% vs. 15%) and complete response (11% vs. 3%).

Younger patients (aged ≤ 70 years) and patients with node-negative disease exhibited greater benefit from ECX compared with the standard chemotherapy regimen, Cunningham said.

Researchers observed a significantly lower incidence of grade 3 or 4 adverse events among patients who received the standard chemotherapy regimen (30% vs. 47%; P < .001).

“The survival in both arms of this trial were better than expected,” Cunningham said. “This is encouraging for patients with esophageal gastric cancer. We are also seeing a trend towards improvement with ECX with regard to tumor regression rates — which were significantly better — and a PFS that was not quite significantly better. This did not, however, translate into a survival advantage.” – by Cameron Kelsall

Reference:

Alderson D, et al. Abstract 4002. Presented at: ASCO Annual Meeting; May 29-June 2, 2015; Chicago.

Disclosure: Cunningham reports receiving research funding from Amgen, AstraZeneca, Celgene, MedImmune, Merck Serono, Merrimack and Sanofi. Please see the abstract for a list of all other researchers’ relevant financial disclosures.

    Perspective

    The important thing to take away from this trial is that anytime we are giving neoadjuvant chemotherapy for any disease, it needs to actually offer a meaningful benefit. With esophageal cancer, surgery is really the most important part of the treatment. This trial looked to see if more chemotherapy would be beneficial — in this case, addition of drugs and doubling the duration of therapy. What we can see is that there was no increase in PFS, DFS, OS or 3-year survival. Although there was some increase in the ability to get a more effective surgery, patient outcomes were not improved. In fact, there was a significant increase in toxicity. Clearly, this is not something we should view as positive from a treatment standpoint. It really just adds toxicity without any clear benefit.

    • Dale Shepard, MD, PhD
    • Cleveland Clinic

    Disclosures: Shepard reports no relevant financial disclosures.

    Perspective

    This study adds more questions to the role of epirubicin in chemotherapy for patients with esophageal and gastroesophageal junction tumors. This study was worthy of exploration given the positive results of the MAGIC trial. There were some trends towards benefit with the epirubicin containing arm — including some higher pathological complete response rates — though this did not translate to a survival benefit. I think it does beg the question: if they had purely looked at four cycles vs. two cycles of the same chemotherapy with only cisplatin and 5-fluouracil, could this have been a more positive study? Fortunately, with the amount of patients they enrolled and the amount of cancer specimens they have, the researchers will be going back to look at some exploratory biomarkers.

    • Joseph Chao, MD
    • City of Hope

    Disclosures: Chao reports no relevant financial disclosures.

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