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Preoperative treatment with 5-fluorouracil and cisplatin may be superior to surgery alone in extending survival of patients with resectable adenocarcinoma of the lower esophagus, esophagogastric junction, or stomach, according to the results of a phase III trial.
At a median follow-up of 5.7 years, the trial's preoperative chemotherapy arm had an overall survival rate of 38% versus 24% in the surgery-only arm of the study (P = .021). Median disease-free survival rates were 34% and 21%, respectively (P = .0033).
Confirming results of the earlier Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) study, these new data suggest that preoperative chemotherapy can significantly increase the number of patients surviving to 5 years and also may increase disease-free survival, said Dr. Valerie Boige, who is the lead author of the trial, which was coordinated by the Fédérale Nationale des Centres de Lutte Contre Le Cancer (FNLCC) based in Paris.
Earlier, the phase III MAGIC trial from Britain found that a perioperative regimen of epirubicin, cisplatin, and 5-fluorouacil, given both before and after surgery, also reduced the risk of death compared with surgery alone (N. Engl. J. Med. 2006;355:11-20).
A primary difference between the two studies is that whereas 75% of patients in the MAGIC trial had gastric cancers, 75% of patients in the current study had esophageal or gastro-esophageal junction tumors.
Although the French trial was designed to test the benefit of preoperative chemotherapy, about half of the patients—primarily those whose disease responded to, or remained stable with, well-tolerated preoperative chemotherapy—also received up to four additional cycles of the same regimen after surgery.
One observer noted that, as with the MAGIC trial, this trial design makes it hard to know exactly how much each part of the perioperative therapeutic approach is contributing to the results.
Between 1995 and 2003, Dr. Boige and her colleagues enrolled 224 patients from 25 centers throughout France in the new clinical trial. All participants had adenocarcinoma, stage II or higher.
The patients were centrally randomized to receive preoperative chemotherapy (n = 113) followed by surgery within 4-6 weeks, or to proceed directly to surgery, said Dr. Boige of the Institut Gustave Roussy in Villejuif.
After surgery about half of the preoperative chemotherapy group also received up to four additional cycles of the same regimen.
Those receiving only surgery had no postoperative treatment.
Key grade 3-4 toxicities in the preoperative chemotherapy arm included neutropenia (20%) and nausea and vomiting (9%).
One patient died from toxicity one month after the first cycle of therapy. Overall, 37% of the patients experienced severe toxicity.
Postoperative morbidity and mortality did not differ significantly between the study arms.
Resections were microscopically complete in three-quarters of those in the surgery group, compared with 87% of those who received chemotherapy first, a difference that was statistically significant.
At baseline, there were no statistically significant differences in the two arms with regard to age (median 61 years), gender (83% men), or performance status (75% WHO of 0).
"In resectable gastroesophageal adenocarcinoma, preoperative chemotherapy with 5-FU and cisplatin significantly increases the curative resection rate and significantly improves overall survival without increasing postoperative morbidity and mortality," Dr. Boige concluded.
In his discussion of the paper from Dr. Boige's group, Dr. David H. Ilson, who is with the Memorial Sloan-Kettering Cancer Center in New York City, agreed that, as has been seen with other trials involving adenocarcinomas, there does appear to be a survival benefit for preoperative chemotherapy with cisplatin and 5-FU.
Dr. Ilson added that, unlike earlier studies, this trial demonstrated a 13% improvement in the rate of R-zero resection with chemotherapy.
The actual impact on tumor downstaging, however, was not statistically significant.
He said the major impact of chemotherapy was to reduce systemic recurrence to 42% from 56% for surgery alone, but local recurrence was not affected.
"And while cisplatin-fluorouracil in this trial were similar to the epirubicin regimen in the MAGIC trial, one could argue that in esophagus and GE junction cancers perhaps epirubicin is not required as part of the chemotherapy cocktail," Dr. Ilson said.
Dr. Ilson also noted that some aspects of the design of the study concerned him.
"The relative small sample size means that differences of 10 to 15 percentage points come down to outcome differences in only 10 to 15 patients.
"Additionally, endoscopic ultrasound was not performed, so we question the accuracy of pretherapy staging on this study, which had no stratification for pretreatment stage."
Boige V. et al. Final results of a randomized trial comparing preoperative 5-fluorouracil (F)/cisplatin (P) to surgery alone in adenocarcinoma of stomach and lower esophagus (ASLE): FNLCC ACCORD07-FFCD 9703 trial. Abstract 4510.
Commentary |
Gastric and gastroesophageal adenocarcinoma is a major worldwide health problem. It is the second leading cause of cancer death internationally, and was responsible for one-eighth of all cancer-related mortality in the world last year. There are well-recognized international variations in disease incidence and mortality, and also questions around whether the disease has different molecular features in some geographic areas. Clinical investigation of systemic therapy in gastric cancer is also an international effort, with well-conducted randomized trials that have altered standards of care coming from North America, Europe, and the Far East. The data presented at ASCO 2007 reflected this, and the articles highlighted here were from European and Japanese investigators. The major advance in the systemic therapy of gastric cancer in the last decade has been demonstration of a survival benefit from the use of adjuvant/neoadjuvant chemotherapy in the perioperative period. The data from Dr. Boige and colleagues adds to the positive data generated by the U.S. postoperative chemoradiotherapy trial (N. Engl. J. Med. 2001;345:725-30) and the European MAGIC trial (N. Engl. J. Med. 2006;355:11-20). While questions still remain about the optimal agents, which stages to treat, the sequencing of systemic therapy and surgery, and the role of radiation therapy, few would dispute that systemic therapy now has a clear role in the management of higher-stage resectable disease. In contrast, improvements in the advanced disease setting have been modest. Survival is significantly better with chemotherapy as opposed to the best supportive care, and the use of combination therapy shows a small but significant advantage over single-agent (usually fluoropyrimidine) therapy. While there are multiple active combination regimens, fluoropyrimidines and platins are key components in almost all. The data from Dr. Narahara provides further confirmation of the benefit of cisplatin, and along with the data from Dr. Boku raises the question of what is the best fluoropyrimidine. Infusional 5-fluorouracil (5-FU) is active and generally well tolerated, but the need for prolonged infusions and long-term venous access is inconvenient for patients—thus, oral fluoropyrimidines such as capecitabine and S-1 are potentially attractive alternatives. S-1 is a pharmacologically interesting drug that has been widely used in Japan for gastrointestinal cancers for some time. The data presented at ASCO suggest further investigation is warranted, and trials comparing S-1 to other fluoropyrimidines in gastric cancer are now underway. The benefits seen will likely be reflected more in toxicity and quality of life than in survival, however. Major advances in metastatic disease are likely to come only with the introduction of novel or targeted agents. The development of such agents in gastric cancer has lagged behind successes in other areas, but gastric cancer is currently the most active area of investigation in advanced disease. — Malcolm J. Moore, M.D.
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