Adjuvant and neoadjuvant treatment of gastric cancer INTRODUCTION — Although the incidence of gastric cancer has been declining steadily since the 1930s, it remains a major cause of cancer death in the United States . The high mortality rate reflects the prevalence of advanced disease at presentation. The five-year survival rate for patients with completely resected early stage gastric cancer is approximately 75 percent while it is 30 percent or less for patients who have extensive lymph node involvement. These sobering results have spawned efforts to improve the treatment results for this group of patients using adjuvant (postoperative) or neoadjuvant (preoperative) radiation therapy (RT) and/or chemotherapy. The positive impact of such therapy on survival in patients with resected gastric cancer has become clearer over time, although there is no consensus as to the best approach. A large American Intergroup trial demonstrating a significant survival benefit for chemoradiotherapy after complete resection resulted in the adoption of this strategy in the United States despite concerns that inadequate surgical staging (particularly the extent of lymphadenectomy) may have led to an overestimation of benefit. However, in many other parts of the world, chemotherapy alone (either adjuvant or combined preoperative and postoperative administration as in the multinational MAGIC trial) is the preferred treatment strategy. The issues surrounding extent of lymph node dissection in gastric cancer are discussed in detail elsewhere. ADJUVANT CHEMORADIOTHERAPY — Interest in adjuvant RT stems from the observation that over 80 percent of patients who die from gastric cancer experience a local recurrence at some time in their illness. The limited data that exist fail to show a survival benefit from the addition of either postoperative or intraoperative RT alone in patients with resected gastric cancer . However, almost all postoperative RT trials have included concurrent chemotherapy (usually with 5-fluorouracil, 5-FU) to improve the efficacy of RT (referred to as "radiation sensitization"). Intergroup trial 0116 — Of the three positive randomized trials, the largest and most recent provides the most compelling data in support of adjuvant chemoradiotherapy following complete surgical resection, particularly since it used contemporary RT techniques and leucovorin-modulated 5-FU. US Intergroup study INT-0116 randomly assigned 556 patients following potentially curative resection of gastric cancer to observation alone or adjuvant combined chemoradiotherapy. Treatment consisted of one cycle of 5-FU (425 mg/m2 per day) and leucovorin (20 mg/m2 per day) daily for five days, followed one month later by 45 Gy (1.8 Gy/day) RT given with 5-FU and leucovorin (400 mg/m2 and 20 mg/m2, respectively) on days 1 through 4, and on the last three days of RT. Radiation fields were subjected to centralized pretreatment review. Two more five-day cycles of chemotherapy (5-FU 425 mg/m2 per day and leucovorin 20 mg/m2 per day) were given at monthly intervals beginning one month after completion of RT. The majority of tumors were T3 or T4 (68 and 69 percent of the treated and control groups, respectively), and 85 percent had nodal metastases. Three-year disease-free (48 versus 31 percent) and overall survival rates (50 versus 41 percent) were significantly better with combined modality therapy, and median survival was significantly longer (36 versus 27 months). Grade 3 and 4 toxic effects occurred in 41 and 32 percent of the chemoradiotherapy group, respectively, while three patients (1 percent) died from treatment-related toxic effects. The most frequent grade 3 or worse adverse effects were hematologic (54 percent), gastrointestinal (33 percent), infectious (6 percent), and neurologic (4 percent). These results changed the standard of care in the United States following potentially curative resection of gastric cancer from observation alone to adjuvant combined chemoradiotherapy, although the optimal regimen for postoperative chemoradiotherapy has not yet been established. This trial included patients with adenocarcinomas of the gastroesophageal junction (GEJ) that extended at least two cm into the stomach, suggesting that some patients with adenocarcinoma of the GEJ may benefit from postoperative therapy. The follow-up Intergroup trial is using this regimen as its standard control arm, although it has changed the chemotherapy given during radiation to continuous infusion 5-FU at a dose of 200 mg/m2 per day during the entire course of radiation. As noted above, a criticism of the American Intergroup trial was the limited extent of the surgical procedure in most cases. Although D2 lymph node dissection (removal of nodes along the hepatic, left gastric, celiac and splenic arteries as well as those in the splenic hilum) was recommended in the protocol, it was only performed in 10 percent of the enrollees, and 54 percent did not even have clearance of the D1 (perigastric) nodal regions. This noncompliance likely contributed to inferior survival and a 64 percent relapse rate in the surgery alone arm. However, support for the benefit of adjuvant chemoradiotherapy even in patients who have undergone a therapeutic D2 lymph node dissection was provided by a retrospective review of 990 Korean patients undergoing potentially curative resection for stage II to IV (not M1) gastric adenocarcinoma, 544 of whom received chemoradiotherapy (the same regimen as in the INT 0116 trial), and 446 did not For all stages of disease, 5-year overall survival and relapse-free survival rates significantly favored the chemoradiotherapy group. Although these data are not derived from a randomized controlled trial, and are subject to several biases, they provide indirect support for the benefit of chemoradiotherapy in adequately surgically staged patients. CHEMOTHERAPY — In contrast to the situation in the United States, the standard of care in many parts of Europe is perioperative chemotherapy while in Japan and Southern Europe, many patients routinely receive postoperative chemotherapy alone Adjuvant chemotherapy — More than 30 randomized trials have compared adjuvant systemic chemotherapy to surgery alone in resectable gastric cancer, with variable results . Several reasons have been proposed to account for these conflicting results:
Meta-analyses — A survival benefit for adjuvant chemotherapy has been supported by at least two meta-analyses, at least one of which was limited to trials from Western countries.
Adjuvant systemic chemotherapy is accepted as routine following surgical resection of gastric cancer in Japan and some parts of Europe, while as noted above, in the United States, adjuvant combined chemoradiotherapy has been adopted as the standard of care, largely as a result of the Intergroup study 0116. In other parts of Europe, a combination of preoperative and postoperative chemotherapy (perioperative chemotherapy) is more commonly recommended. Neoadjuvant chemotherapy — Neoadjuvant chemotherapy is typically administered as a means of "downstaging" a locally advanced tumor prior to an attempt at curative resection. This approach has been applied to patients thought to have resectable disease as well as those with apparently unresectable but nonmetastatic disease. Another benefit of administering neoadjuvant chemotherapy prior to an exploration for resection is that patients who have a high likelihood of developing distant metastases (ie, those with bulky T3/T4 tumors, visible perigastric nodes by preoperative imaging studies including endoscopic ultrasound [EUS], a linitis plastica appearance, or positive peritoneal cytology in the absence of visible peritoneal disease) may be spared the morbidity of unnecessary gastrectomy if they demonstrate evidence of distant metastases after two cycles of chemotherapy. Although phase II trials suggest favorable results from this approach using a variety of different chemotherapy regimens , true benefit can only be assessed in randomized trials. At least four such trials have compared neoadjuvant chemotherapy with surgery alone, only two of which have been published in final form . MAGIC trial — The largest and most influential trial is the United Kingdom Medical Research Council MAGIC trial, in which 503 patients with potentially resectable gastric (74 percent), distal esophageal (11 percent), or GE junction adenocarcinomas were randomly assigned to surgery alone, or surgery plus perioperative chemotherapy (three preoperative and three postoperative cycles of epirubicin, cisplatin and infusional 5-fluorouracil [ECF]) A higher proportion of chemotherapy-treated patients with gastric cancer who underwent radical surgery had a potentially curative procedure (79 versus 70 percent), and significantly more had T1/2 tumors (52 versus 37 percent) and N0/N1 disease (84 versus 71 percent). Chemotherapy was well tolerated overall; excluding patients with neutropenia (23 percent), fewer than 12 percent of all patients had serious (grade 3 or 4) toxic effects. Despite this, only 104 (42 percent) were able to complete protocol treatment, including surgery and all three cycles of the postoperative chemotherapy. These data underscore one of the major problems with the neoadjuvant approach, which is the difficulty in administering the full number of chemotherapy cycles. Nevertheless, with median four-year follow-up, progression-free survival was significantly worse in the surgery alone group (hazard ratio [HR] 0.66) as was overall survival (HR 0.75). The 25 percent reduction in the risk of death favoring chemotherapy translated into an improvement in five-year survival from 23 to 36 percent. Local failure occurred in 14 percent of the chemotherapy-treated patients compared to 21 percent of those undergoing surgery alone. Distant metastases developed in 24 and 37 percent of patients, respectively. Dutch trial — In contrast to these results, a benefit for neoadjuvant chemotherapy could not be shown in a small Dutch trial, in which 56 patients with apparently operable gastric cancer were randomly assigned to four cycles of FAMTX followed by surgery or surgery alone. Forty-four percent could not complete the neoadjuvant chemotherapy, and the rate of "curative" resections actually favored the surgery alone group (62 versus 56 percent) The trial was criticized in that routine abdominal CT and staging laparoscopy were optional; as a result of understaging, many patients likely had metastatic disease at the time of enrollment. Summary — Despite the negative Dutch trial, the impressive results of the well conducted MAGIC trial have led to the adoption of the perioperative chemotherapy approach in much of Europe and other parts of the world. Whether these results have changed (or should change) practice in the United States is more difficult to address. The results of the MAGIC trial are not directly comparable to those of INT 0116, as patients were randomized prior to surgery compared to after complete resection in INT 0116. However, the magnitude of the difference between surgery alone and the treatment arms of both studies are similar. A major problem in the United States is that patients with gastric cancer are commonly taken to the operating room prior to consultation by medical or radiation oncologists. Multidisciplinary preoperative evaluation is preferable. The incidence of local failure in the chemotherapy arm of the MAGIC trial, while not as high as in the surgery arm, was an important component of failure. This suggests that adding RT to ECF might be even more advantageous. An ongoing United States Intergroup study, CALGB 80101, compares postoperative ECF before and after 5-FU plus concurrent RT versus the INT 0116 protocol regimen (bolus 5-FU and leucovorin with 5-FU plus concurrent RT). Enrollment is available through the Clinical Trials Support Unit (CTSU) and eligible patients should be encouraged to participate. Intraperitoneal chemotherapy — The observation that resected gastric cancer tends to recur within the peritoneum has provided the rationale for the evaluation of adjuvant intraperitoneal (IP) chemotherapy. Although preliminary reports demonstrated feasibility and safety, the results of randomized studies (most of which include a mix of patients with resected stage III and IV disease, have been mixed:
Thus, in our view and that of others , this technique remains investigational. NEOADJUVANT APPROACHES FOR PATIENTS WITH LOCALLY ADVANCED BUT INITIALLY UNRESECTABLE DISEASE — The optimal management of patients with locally advanced unresectable but nonmetastatic gastric cancer is uncertain, and there is no standard approach. Palliation for local symptoms and systemic chemotherapy are discussed elsewhere. Preoperative chemoradiotherapy — Preliminary uncontrolled data suggest that with preoperative combined modality therapy (chemoradiotherapy with or without induction chemotherapy), approximately 70 percent of patients with localized but initially unresectable gastric cancer, can undergo potentially curative resection, with pathologically complete response rates as high as 30 percent . Although these early data seem encouraging, the studies have been conducted in highly selected patients, and randomized trials will ultimately be necessary to confirm benefit from any of these approaches over chemoradiotherapy alone. Preoperative
chemotherapy alone — Likewise, the benefit of neoadjuvant chemotherapy in
patients who are deemed initially unresectable but without distant metastatic disease is
uncertain. At least three studies have explored the use of preoperative chemotherapy for patients with locally advanced gastric cancer without distant metastases. All have shown that some patients initially thought to be unresectable respond to chemotherapy sufficiently that they are able to undergo potentially curative surgery. However, pathological complete response rates are low, around 5 percent at best. Unresectable nonmetastatic gastric cancer is usually treated primarily with chemotherapy, as is metastatic disease. Therefore, although not a standard approach, such treatment may render some patients resectable. Confirmatory studies of preoperative chemotherapy alone among this patient subgroup, and trials evaluating the use of concurrent chemoradiotherapy are warranted. SUMMARY AND RECOMMENDATIONS — The poor long-term survival rates after surgery alone in patients with gastric cancer have led to the exploration of a variety of adjuvant (postoperative) and neoadjuvant (preoperative) treatment strategies incorporating chemotherapy and radiation therapy (RT). The survival benefit from combined modality therapy has become more clear over time, although there is no consensus as to the optimal approach. We prefer that eligible patients be enrolled on the ongoing United States Intergroup study, CALGB 80101, which compares the INT-0116 protocol regimen (bolus 5-FU and leucovorin with 5-FU plus concurrent RT) versus postoperative ECF before and after 5-FU plus concurrent RT. Enrollment is available through the Clinical Trials Support Unit (CTSU) For patients in whom protocol participation is not feasible, and who have already undergone potentially curative gastric resection, we suggest adjuvant chemoradiotherapy based upon the results of US Intergroup trial 0116 Although the optimal regimen has not been established, we use the treatment arm of INT-0116 as our standard protocol. (
An acceptable alternative approach for patients who are seen prior to surgical resection is chemotherapy alone. Although the optimal regimen and timing (preoperative and/or postoperative) remains to be defined, combined preoperative and postoperative ECF chemotherapy (as was used in the MAGIC trial), is reasonable. Since this regimen has not been compared head-to-head with standard postoperative chemoradiotherapy, it is not known whether this approach is superior to postoperative chemoradiotherapy. There is insufficient evidence from randomized trials to recommend intraperitoneal chemotherapy, and we suggest not pursuing this approach outside of the context of a clinical trial |