In patients with inoperable esophageal cancer, definitive chemoradiotherapy offers a curative treatment option. A trial comparing 2 different regimens for the chemotherapy component of this treatment found that there was no significant difference in survival, but found other reasons to favor one of the regimens over the other.
Definitive chemoradiotherapy using fluorouracil plus leucovorin and oxaliplatin (FOLFOX) is an easier, less toxic, and cheaper option than chemoradiotherapy with fluorouracil and cisplatin, the researchers note.
The results come from the phase 2/3 PRODIGE5/ACCORD17 trial, published in the March issue of the Lancet Oncology.
"FOLFOX with radiotherapy is a convenient choice for patients for whom a nonoperative approach is selected," said first author Thierry Conroy, MD, chief executive officer at the Institut de Cancérologie de Lorraine in Vandoeuvre-lès-Nancy, France.
"Not only is it more convenient than fluorouracil and cisplatin, the FOLFOX regimen reduces some toxicities, such as mucositis, alopecia, and renal insufficiency, and lowers the risk of toxic deaths," Dr. Conroy told Medscape Medical News.
Another advantage of the FOLFOX regimen is that it can be administered in the outpatient setting, he noted.
In an accompanying comment, Bryan Burmeister, MD, from Princess Alexandra Hospital in Brisbane, Australia, writes that even though the study did not show an improvement in progression-free survival, it has "potentially shown an improvement in the therapeutic ratio by increasing the treatment options for cisplatin-intolerant patients, and reducing the burden of treatment cost through a less time-consuming and easier to administer regimen — and thus, potentially, improving quality of life for patients."
Comparing the 2 Regimens
Dr. Conroy and his group sought to determine whether progression-free survival in patients with nonoperable localized esophageal cancer could be improved by replacing cisplatin with FOLFOX in the standard chemotherapy regimen.
The open-label parallel-group trial involved patients 18 years and older treated at 1 of 24 centers in France from October 2004 to August 2011.
All had previously untreated stage I to IVA squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the esophagus. They were deemed unsuitable for surgery if they had disease that was potentially nonresectable, comorbidities that precluded surgery, or chose not to have surgery.
In the study cohort, Eastern Cooperative Oncology Group (ECOG) status ranged from 0 to 2, and all patients had sufficient caloric intake and adequate hematologic, renal, and hepatic function.
Patients were randomly assigned to 1 of 2 treatments: the FOLFOX regimen consisted of 134 patients in the intent-to-treat population and 131 patients in the safety population; the fluorouracil plus cisplatin regimen consisted of 133 patients in the intent-to-treat population and 128 patients in the safety population.
The safety population actually received the study drugs.
The FOLFOX regimen involved 6 cycles of oxaliplatin 85 mg/m², leucovorin 200 mg/m², bolus fluorouracil 400 mg/m², and infusional fluorouracil 1600 mg/m², delivered over 46 hours. The first 3 cycles were given concurrently with radiotherapy.
The fluorouracil plus cisplatin regimen involved 4 cycles of fluorouracil 1000 mg/m² per day for 4 days and cisplatin 75 mg/m² on day 1. Two of the cycles were given concurrently with radiotherapy.
All patients received 50 Gy radiotherapy delivered in 25 fractions (5 fractions per week).
The patients were followed for a median of 25.3 months.
There was no significant difference in median progression-free survival with the FOLFOX and fluorouracil plus cisplatin regimens (9.7 vs 9.4 months; P = .64). There was also no significant difference in median overall survival (20.2 vs 17.5 months; P = .70).
More Toxic Deaths With Fluorouracil Plus Cisplatin
However, there was a significant difference in the number of toxic deaths between the FOLFOX and fluorouracil plus cisplatin regimens (1 vs 6; P = .066).
Rates of grade 3/4 adverse events were not significantly different with the FOLFOX and fluorouracil plus cisplatin regimens. However, paraesthesia (47% vs 2%), sensory neuropathy (18% vs 1%), elevated aspartate aminotransferase concentrations (11% vs 2%), and elevated alanine aminotransferase concentrations (8% vs 2%) were more common with FOLFOX, and serum creatinine increases (3% vs 12%), mucositis (27% vs 32%), and alopecia (2% vs 9%) were more common with fluorouracil plus cisplatin.
"No difference in efficacy outcomes was noted for patients receiving chemoradiotherapy with FOLFOX and those receiving it with fluorouracil and cisplatin," Dr. Conroy reported.
However, "our data suggest that the FOLFOX regimen might be an alternative to the fluorouracil and cisplatin combination with concurrent radiotherapy in patients with localized esophageal cancer, because FOLFOX might be easier and more convenient to administer than the fluorouracil and cisplatin regimen. We feel that chemoradiotherapy including FOLFOX could therefore be used safely as an alternative treatment in this setting," he added.
Unsurprising Result
Because only 259 patients actually received the study drugs, the trial was underpowered, and the fact that there was no significant difference in progression-free survival was not surprising, Dr. Burmeister notes in his comment.
There were also no significant differences between the regimens for overall survival, proportion of endoscopic complete response, time to treatment failure, and occurrence of grade 3/4 toxic events, he points out.
In the past, patients who were cisplatin-intolerant have been treated with radiotherapy alone or with combinations of radiotherapy and nonplatinum-containing regimens, but most of these treatments have worse survival outcomes than standard chemotherapy, Dr. Burmeister writes.
In addition, high inpatient and outpatient admission rates are linked to cisplatin because of dehydration, meaning that there is a potential cost benefit to not including cisplatin in a treatment regimen.
"I commend the authors for completing this multicenter trial given its implications for the future management strategies for esophageal cancer," Dr. Burmeister concludes.
"It sets the scene for further randomized trials designed to test similar end points with other treatment regimens that contain platinum, such as a regimen of carboplatin, paclitaxel, and radiotherapy, which has been effective in the neoadjuvant treatment of operable esophageal carcinoma, and has low toxicity," he adds.
He urges the authors to publish their quality-of-life data. "A study of this type would be more complete with this additional data, which could enhance the argument for replacement of cisplatin with oxaliplatin."
The study was funded by UNICANCER, the French Health Ministry, sanofi-aventis, and the National League Against Cancer. Dr. Conroy reports receiving honoraria from sanofi-aventis. Dr. Burmeister has disclosed no relevant financial relationships.
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