Chemotherapy Before Surgery May Increase Survival in Stomach Cancer
Stomach (gastric) cancer, esophagogastric junction. (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary.)
Confirming findings from an earlier study, chemotherapy given before surgery for cancer of the lower esophagus and stomach increased the number of patients surviving for five years compared to surgery alone. Those receiving chemotherapy also had better disease-free survival, and the side effects from the treatment were considered manageable.
American Society of Clinical Oncology (ASCO) annual meeting, Chicago, June 3, 2007 (see the meeting abstract). Trial results were published in the May 1, 2011, Journal of Clinical Oncology; see the journal abstract.
Surgery is usually the primary treatment for adenocarcinoma arising in the area of the digestive system which includes the stomach, the lower esophagus leading into the stomach, and the part where they meet (the esophagogastric junction). But surgery alone doesn’t produce many cures because by the time the disease is diagnosed in most patients, it has already spread into adjacent tissues and organs or to more distant sites in the body. The chances of surviving five years after surgery range from 5 to 30 percent, and thus researchers are actively looking for additional treatment strategies.
In 2001, a large, randomized, U.S. Intergroup phase III clinical trial showed that the risk of death was significantly reduced in stomach (gastric) cancer patients who received adjuvant (after surgery) chemotherapy along with radiation therapy. In 2006, the European MAGIC phase III clinical trial (see a summary of the trial) showed that combination chemotherapy using epirubicin, cisplatin, and 5-fluorouracil (ECF), given both before and after surgery (perioperative), also reduced the risk of death compared with surgery alone.
The French clinical trial described below was similar to MAGIC, except that patients were randomly assigned either to surgery alone or to chemotherapy before surgery (preoperative); also, the chemotherapy combination was CF only, without epirubicin.
Between 1995 and 2003, investigators enrolled 224 stomach cancer patients from 25 centers throughout France in this phase III clinical trial. All patients had adenocarcinoma, stage II or higher. The cancer occurred in the lower third of the esophagus (11 percent), at the esophagogastric junction (64 percent), or in the stomach itself (25 percent). Patients averaged 63 years of age, and most were men. Stomach cancer occurs twice as often in men as in women.
Patients were randomly assigned to receive either surgery or preoperative chemotherapy followed by surgery. The preoperative chemotherapy-plus-surgery group received cisplatin in combination with a continuous infusion of 5-fluorouracil. Surgery followed within four to six weeks.
After surgery about half of the preoperative chemotherapy group – mainly those whose disease responded to, or remained stable with, preoperataive chemotherapy and who tolerated it well – also received up to four more cycles of the same regimen after surgery (post-operative chemotherapy). Those receiving surgery alone had no post-operative treatment.
Valérie Boige, M.D., was the lead author for the study (the ACCORD 07-FFCD 9703 trial) which was coordinated by the Fédérale Nationale des Centres de Lutte Contre Le Cancer (FNLCC), based in Paris.
Patients were followed for a median of 5.7 years. The five-year overall survival rate for those treated with surgery alone was 24 percent, compared to 38 percent for those who also received preoperative chemotherapy-plus-surgery, a risk reduction of 31 percent. After five years, 34 percent of the preoperative chemotherapy-plus-surgery group were disease free, compared to 21 percent for the surgery-alone group, which amounted to a 35 percent reduction in risk.
Side effects of the preoperative chemotherapy included one treatment-related death, a significant drop in white blood cells in 20 percent of patients, and fairly severe nausea and/or vomiting in nine percent. Altogether, 37 percent of those receiving preoperative chemotherapy had one or more severe side effects.
Confirming the results of the MAGIC trial, the French study makes “clear that surgery alone for these patients is not enough,” said David H. Ilson, M.D., Ph.D., of the Memorial Sloan-Kettering Cancer Center, in a discussion of the results at the ASCO meeting. He noted that significantly more patients who had chemotherapy prior to surgery went on to have successful surgery.
Although the French trial described here was designed to test the benefit of preoperative chemotherapy, a significant number of patients also received chemotherapy after surgery. The earlier MAGIC trial was designed to test the benefit of chemotherapy given both before and after surgery.
"The designs of both [the French and MAGIC] trials makes it hard to know exactly how much each part of the perioperative approach is contributing to the results,” noted Margaret Mooney, M.D., of the National Cancer Institute’s Cancer Therapy Evaluation Program. She and Ilson look forward to trials now underway in Europe that will make sharper comparisons between all of the components.
In addition, they said, more must be learned about whether chemotherapy, both before and after surgery (the European approach) or chemotherapy plus radiotherapy after surgery (the U.S. approach) works best.