Adjuvant and Neoadjuvant Therapy for Gastric Cancer: Taking Stock of the Options

The number of evidence-based adjuvant and neoadjuvant treatment options for gastric cancer has been increasing. This increase has given rise to a practical difficulty: How should clinicians weigh and choose among the various available options for gastric cancer?

For the past several years, two options have been widely accepted as standards of care for gastric cancer: postoperative chemoradiation and perioperative chemotherapy. The randomized Intergroup 0116 trial showed that postoperative 5-fluorouracil (5-FU)/ leucovorin–based chemoradiation increases overall survival in comparison with surgery alone.¹ A recent update of this trial, with a more than 10-year median follow-up, again showed a significant improvement in overall survival with postoperative chemoradiation.² A few years after the initial publication of the Intergroup trial, the MAGIC trial reported an improvement in overall survival with perioperative epirubicin, cisplatin, and 5-FU (ECF), compared with surgery alone, thus establishing perioperative chemotherapy as another standard of care for resectable gastric cancer.³

Results of recently published trials indicate that adjuvant chemotherapy could represent yet another acceptable treatment option for gastric cancer. The CLASSIC trial from South Korea showed that adjuvant chemotherapy with capecitabine and oxaliplatin improves 3-year disease-free survival when compared with surgery alone.⁴ Moreover, 5-year results from the ACTS trial showed that adjuvant chemotherapy with S-1 improves overall survival when compared with surgery alone.⁵ Of note, both the CLASSIC and ACTS trials were performed in patients who underwent D2 gastrectomy, and therefore, these results may not be generalizable to those treated with more limited nodal dissections. Further, the CLASSIC trial has so far reported a benefit only in disease-free survival, not in overall survival, unlike the Intergroup and MAGIC trials discussed earlier.

There is no consensus about the benefit of adding radiation therapy in patients receiving preoperative or postoperative chemotherapy. The randomized European CRITICS trial is evaluating the addition of radiation to preoperative chemotherapy.⁶ In this trial, patients are treated with 3 cycles of epirubicin, cisplatin, and capecitabine (ECC), followed by surgery and either 3 additional cycles of ECC or radiation therapy with concurrent cisplatin and capecitabine. Results from this ongoing trial will clarify whether radiation therapy provides an incremental benefit when added to a chemotherapy regimen similar to that used in the MAGIC trial. In a South Korean randomized trial, the ARTIST trial, the benefit of adding radiation to postoperative chemotherapy was investigated.⁷ In this trial, patients who underwent D2 gastrectomy were randomized to receive either 6 cycles of cisplatin and capecitabine or 4 cycles of cisplatin and capecitabine and radiation therapy with concurrent capecitabine. Although there was no significant difference in disease-free survival between the two arms overall, subgroup analysis indicated that, in node-positive patients, radiation therapy improved disease-free survival, when compared with chemotherapy alone. Hence, it is quite possible that radiation therapy would provide a benefit when added to postoperative chemotherapy in certain subgroups of patients such as those who are node-positive and others who are at high-risk of locoregional recurrence. Moreover, since the ARTIST trial was performed in patients with D2 lymphadenectomy, the results are not applicable to those undergoing limited nodal dissections who may be at higher risk of locoregional recurrence and may benefit more from radiation therapy.

In this issue, Chakravarthy et al report results from the ECOG E7296 trial, a multi-institutional phase II trial of preoperative chemotherapy with 3 cycles of paclitaxel and cisplatin, followed by surgery and postoperative 5-FU/leucovorin-based chemoradiation. The preoperative chemotherapy regimen in this trial had a high rate of toxicity, with 34% grade 3 and 32% grade 4 toxicity. The preoperative regimen was also associated with a relatively poor response rate, with no patient having pathologic complete response. However, these toxicity and response rates reflect the specific agents and doses used in this trial; no interpretations should be drawn about the potential role of preoperative chemotherapy solely on the basis of these results. In this trial, patients had to reregister for postoperative therapy according to certain criteria, such as margin status and number of examined nodes. Only 10 patients reregistered for the postoperative component of the trial, of whom only 7 received any postoperative treatment and only 3 completed chemoradiation. With these small numbers of patients, it is difficult to draw any conclusions about postoperative therapy. Given the limitations of the ECOG E7296 trial, the results should not be taken as a testament against the overall approach of preoperative chemotherapy and postoperative chemoradiation. Indeed, the same approach is being studied with different chemotherapeutic agents in the CRITICS trial discussed earlier.

In the ECOG E7296 trial, 60% of patients had Siewert type I or II gastroesophageal junction adenocarcinoma. We now have strong randomized evidence for the role of preoperative chemoradiation in this subgroup. In the Dutch CROSS trial, patients with esophageal and gastroesophageal junction adenocarcinoma were randomized to receive surgery alone or preoperative radiation therapy with concurrent carboplatin and paclitaxel, followed by radiation therapy.⁸ The median overall survival in the preoperative chemoradiation arm was more than double that in the surgery-alone arm.

Thus, we now have a variety of treatment options for gastric and gastroesophageal junction cancer, all backed by randomized trials: postoperative chemoradiation, perioperative chemotherapy, postoperative chemotherapy, and preoperative chemoradiation. Given this wide variety of choices, our task becomes knowing which option is most applicable to each clinical situation. For patients with tumors involving mainly the gastroesophageal junction, preoperative chemoradiation represents a very effective treatment. In patients with tumors in the rest of the stomach, those seen before surgery could be considered for either perioperative chemotherapy or upfront surgery, followed by postoperative treatment. In patients seen after surgery with a sub-D2 dissection with no prior therapy, postoperative chemoradiation would be the preferred choice. In patients seen after surgery with a D2 dissection and no prior therapy, either postoperative chemoradiation or postoperative chemotherapy could be considered, with the caveat that the addition of radiation to postoperative chemotherapy may be beneficial in certain subgroups, such as node-positive patients. In all cases, a multidisciplinary discussion would be ideal to facilitate selection of the most effective treatment for each patient.