The majority of patients who undergo resection for gastric cancer experience relapse and ultimately die of their disease. Therefore, considerable attention has been paid to neoadjuvant and adjuvant strategies to improve surgical outcomes. Two different approaches have been tested in major clinical trials conducted in the past several years: Postoperative chemoradiotherapy was assessed in a US Southwest Oncology Group/Intergroup study (SWOG 9008/INT 0116), and perioperative chemotherapy was studied in a UK Medical Research Council (MRC) randomized trial (the MRC Adjuvant Gastric Infusional Chemotherapy [MAGIC] trial). These trials demonstrated statistically significant survival benefits in patients with resectable gastric cancer. This review will consider these trials and their implications for clinical practice.
The article by Drs. Jackson, Mochlinski, and Cunningham is a timely review of the current state of practice in the adjuvant treatment of gastric cancer, a common and deadly disease. Unlike breast and colon cancer, where early detection has a significant impact on outcome, few patients with gastric cancer are actually cured by surgery alone. The data for gastric cancer suggest that even early-stage disease has a poor prognosis.
The concept of using additional therapies to improve both local control and management of systemic metastasis in gastric cancer is obviously attractive. After decades of clinical research, we finally have two positive clinical trials that demonstrate a clinically significant benefit to patients with localized gastric cancer. The problem is that these trials give us conflicting clinical strategies to follow and leave us in the clinic with some confusion as to an optimum approach. This article does a nice job of explaining the two approaches but is somewhat lacking in terms of recommendations on how to proceed from here.
As in any adjuvant setting, it would be most valuable for us to understand which patients actually need adjuvant therapy. Following surgical resection, a subgroup of patients clearly is cured by the surgery alone and, therefore, cannot benefit from adjuvant therapy. If we could develop techniques to define this population, then we would make immediate progress by preventing patients from undergoing unnecessary chemotherapy and radiation.
On the other hand, it would be equally useful (although much more difficult) if we could define a subpopulation of patients who, despite receiving standard adjuvant chemotherapy or radiation, would fail to benefit due to resistance. Thus, one of the goals that remains lost is the definition of the population who will respond to chemotherapy and radiation. When we look at these two clinical trials, only a small subgroup is seen to benefit. By predefining this group, our progress will be much more rapid.
Sorting Out the Data
The two clinical trials presented in this review suggest that both chemotherapy and radiation have a role in the perioperative setting. The problem is that the trials give us two different regimens and dramatically different strategies, both yielding positive results. While the radiation therapy used in the intergroup trial may be making up for less than optimal surgery, no study has clearly demonstrated that radiation is required in the postoperative adjuvant setting. Likewise, the European MRC Adjuvant Gastric Infusional Chemotherapy (MAGIC) study does not incorporate radiation at all, but uses multiagent chemotherapy.
So what are we to do when faced with a gastric cancer patient? Just this week I saw one such patient seeking a third opinion. He had been given recommendations ranging from no further therapy, to fluorouracil (5-FU) alone, to ECF (epirubicin [Ellence], cisplatin, 5-FU) postchemoradiation and surgery, and I was supposed to sort it all out.
If we add the results of the two trials together, they suggest there may be a role for neoadjuvant chemotherapy and possibly for neoadjuvant radiation therapy, as in other gastrointestinal cancers such as those of the esophagus and rectum. Unfortunately, the currently ongoing randomized clinical trial does not address this issue, as all patients are being treated postoperatively. A study evaluating neoadjuvant chemotherapy and radiation therapy followed by surgery and more chemotherapy would seem to be ideal, given the results of these two clinical trials.
In the United States, only a portion of oncologists see patients in the preoperative setting. When patients are seen preoperatively, it is recommended that they undergo adequate staging, which today probably includes an endoscopic ultrasound. Certainly the prognosis in a node-positive gastric cancer patient is quite poor with surgery alone and would support a role for chemotherapy given initially. This approach helps identify the population who will be chemotherapy-sensitive and may help define a plan of attack, proceeding through surgery and possibly radiation therapy.
At present, the question I struggle with most is whether one should also use neoadjuvant radiation in an off-protocol setting? Data are emerging for cancers of the distal esophagus that suggest that neoadjuvant radiation and chemotherapy together may offer improvements in outcomes. Given the lack of data to support this, however, it is most likely that radiation therapy would be given in the postoperative setting.
If one were going to play the odds, then a logical approach would be to start with a few cycles of combination chemotherapy in a neoadjuvant setting. For those patients who remain surgical candidates (which should be a high percentage), an operation would be performed. Following this operation, one could consider giving combined-modality chemotherapy and radiation, and possibly additional combination chemotherapy. While there is no direct evidence to support this, I would challenge all of us, as oncologists, to consider what regimen we would devise for ourselves in the same situation.
In summary, we do not have clarity on the issue of the current management of gastric cancer. There is confusion about what regimens are optimum, whether or not radiation should be given, and the timing of these therapies in relation to the surgery. However, we can say that chemotherapy and probably radiation therapy offer benefits to patients in the adjuvant setting. As we move forward, I again urge that we focus on defining the subgroup that will most benefit from chemotherapy, and optimize our treatments in this group.
-John L. Marshall, MD
Dr. Marshall is a speaker and advisor for Sanofi-Aventis, Pfizer, Genentech, Bristol-Myers Squibb, ImClone, and Roche.