Gastric cancer remains one of the most common cancers worldwide. In the United States, approximately 21 000 new cases of gastric cancer will be diagnosed in 2010 with estimated 10 570 deaths attributable to this type of cancer . In contrast to Japan, routine screening of gastric cancer is usually not performed in the United States, primarily, because of its low incidence. Consequently, most patients in the United States present at more advanced stages. The 10-year survival of gastric cancer for all stages of disease is only 20% . Over the past two decades, efforts have been made to improve surgical techniques, adjuvant chemotherapy, preoperative chemotherapy and radiation. However, none of these approaches have demonstrated a potential alteration of the natural history of this disease. The Southwest Oncology Group (SWOG) 9008/INT 0116 trial, as first reported in 2001, showed a survival benefit for adjuvant chemoradiation, which has become the new standard of care in the United States for resected stage IB-IVM0 gastric cancer . Most recently, the results of the UK Medical Research Council Adjuvant Gastric (MAGIC) trial showed survival benefit of perioperative chemotherapy over surgery alone . In this review, we focus on multidisciplinary approaches in managing localized gastric cancer and new development in treating metastatic disease.
Complete surgical resection remains the only curative modality for early stage gastric cancer. The goals of resection are based on the en-bloc removal of the primary tumor along with any direct extension and the removal of the nodal basins at risk for metastasis. Issues investigated and debated over the past 20 years have focused on the extent of primary resection and the extent of regional lymphadenectomy (D1 vs. D2 dissection) with the goal of delivering an optimal cancer operation while limiting morbidity.
In Japan, D2 lymphadenectomies are routinely performed. Recently, more extended lymphadenectomies such as D3 or even D4 have also been practiced. The superiority of stage adjusted 5-year survival rates in Japan compared with the United States and Europe may be due to more extensive lymph node dissections . To explore whether surgical technique alone influences clinical outcomes in Western population, three major randomized prospective studies have been conducted. Bonenkamp et al.[6,7] reported the first randomized study to compare D1 and D2 dissection in Western population known as the ‘Dutch trial’. Between 1989 and 1993, a total of 711 patients were randomized to receive either D1 or D2 resection with curative intent (380 patients in D1 group and 331 in D2 group). At a median follow-up of 5 years, the overall survival (OS) rates were similar between D1 and D2 groups (45% for D1, 47% for D2, P = 0.99). However, the complication rate, length of hospital stay, and the postoperative mortality were significantly higher in the D2 group . The results of this trial were recently updated. After 11 years of follow-up, there is no statistical difference in OS (30% in D1, 35% in D2, P = 0.53). Again, morbidity (25% for D1, 43% for D2, P < 0.001) and mortality (4% for D1, 10% for D2, P = 0.004) were significantly higher in the D2 group. Further subset analysis revealed a trend favoring D2 dissection in patients with N2 disease, although this benefit did not reach statistical significance . A major limitation of this trial was poor quality control of participating surgeons with adequate expertise in D2 dissections. Nevertheless, this large multicenter trial provides the first randomized comparison of D1 and D2 dissection in gastric cancer.
The British Medical Research Council (MRC) ST01 was also designed to address the same question . In this randomized prospective study, 737 patients were registered and underwent staging laparotomy. Of these, 400 eligible patients were randomized to either D1 or D2 surgery. The 5-year OS rates were similar between D1 and D2 groups (35% for D1, 33% for D2). Similar to the Dutch trial, splenectomy and pancreatectomy were independently associated with poor survival.
A more contemporary trial conducted by the Italian Gastric Cancer Study Group (IGCSG) showed that D2 dissections with pancreas preservation are safe . Seventy-six patients were randomized to D1 and 86 to D2 resections with pancreas preservation. Postoperative complications were comparable between D1 and D2 groups (10.5% for D1, 16.3% for D2, P = 0.29). The overall postoperative mortality rate was 0.6%. The low mortality rate in the study demonstrated that D2 dissection with pancreas preservation is well tolerated and feasible.
Despite these negative large randomized studies, most physicians consider that D2 dissections are advantageous because of more precise staging. The stage migration phenomenon was first reported by Bunt et al. in 1995. An analysis of the surgical specimens from the Dutch trial demonstrated that about 61 to 75% of patients in D1 dissection group were understaged. Hence, the differences between different surgical approaches not only impact the long-term survival but also may confound adjuvant chemotherapy or radiotherapy treatment effects.
Although standard D2 dissection is not supported by these randomized trials, extended lymphadenectomy with pancreas and spleen preservation (known as ‘over-D1’) is generally practiced at major centers in the United States. The overall mortality rate is low. Currently, no consensus has been reached on what constitutes an optimal lymphadenectomy for gastric cancer. More extended lymphadenectomy such as D3 lymphadenectomy, which includes the lymph node dissection to include the para-aortic and celiac lymph nodes, has not been able to demonstrate survival benefit in a randomized trial . The National Comprehensive Cancer Network (NCCN) guideline recommends at least 15 lymph nodes to be examined.
Gastric cancer frequently manifests with local and systemic recurrence after curative surgical resection. Hence, postoperative therapy with chemoradiation was explored. Chemoradiation has shown some encouraging results but has not translated into an OS benefit in some of the early small studies [13,14]. INT-0116 is a well designed phase III randomized trial in which 603 patients with resected adenocarcinoma of the stomach or gastroesophageal junction (stages IB-IVM0) were randomized to either observation or combined modality therapy consisting of five monthly cycles of bolus chemotherapy with 45 Gy radiotherapy concurrent with cycles 2 and 3 . 5-Fluorouracil (425 mg/m2) and leucovorin (20 mg/m2) (5-FU/LV) were administered for 5 consecutive days. Radiotherapy was initiated 28 days after the first cycle of chemotherapy, during which a lower dose of 5-FU was administered (400 mg/m2) concomitantly with leucovorin on the first 4 and last 3 days of adjuvant radiotherapy. One month after completion of radiotherapy, two additional cycles of chemotherapy were administered monthly.
Patients in the INT-116 trial represented a high-risk group and 85% of the patients in both arms had lymph node involvement. After a median follow-up of 5 years, 3-year relapse-free survival rates (48 vs. 31%, P < 0.001), and hazard ratio for relapse [1.52, 95% confidence interval (CI) 1.23–1.86], significantly favored adjuvant chemoradiotherapy. More significantly, OS rates (50 vs. 41%, P = 0.005), hazard ratio for death (1.35, 95% CI 1.09–1.66), and median OS (36 vs. 27, P = 0.0005) were also significantly improved in the chemoradiation group. In the initial analysis, the incidence of adverse grade 3–4 toxicities with chemoradiotherapy was 41 and 32%, respectively. Of these, the most predominant toxicities were hematologic (54%) and gastrointestinal (33%). The most common hematologic toxicity was leucopenia. The most common grade 3–4 gastrointestinal toxicities reported were nausea, emesis, and diarrhea. Mortality was uncommon occurring in only three patients (1%).
Outcome data in this trial were updated in January 2004 after a median follow-up of 7 years . The major endpoints of the trial; OS (hazard ratio = 1.31, 95% CI 1.08–1.61) and disease-free survival (DFS) (1.52, 95% CI 1.25–1.85) were unchanged from the initial analysis. This updated analysis also demonstrated that adjuvant chemoradiation for gastric cancer was not associated with late toxic events.
The trial has been criticized for its surgically undertreated patients. The majority of the patients (54%) in the trial had D0 resections and only 10% patients received D2 dissections. The most recent adjuvant chemoradiation study, CALGB 80101, has completed its accrual. The survival data are awaited. Nevertheless, postoperative chemoradiation with 5-FU/LV remains the standard care in the United States.
The results of adjuvant chemotherapy in gastric cancer have been disappointing. A number of randomized studies conducted over the last three decades have failed to show a consistent survival benefit [16–20]. Perhaps, the results from a Japanese adjuvant trial are most intriguing . A total of 1059 patients with stage II or III gastric cancer who underwent D2 surgical resection were randomized to either observation or 1-year oral S-1 adjuvant therapy. S-1 (Taiho Pharmaceutical, Princeton, New Jersey, USA) is an orally active combination of tegafur (a prodrug that is converted by cells to fluorouracil), gimeracil (an inhibitor of dihydropyrimidine dehydrogenase, which degrades fluorouracil), and oteracil (which inhibits the phosphorylation of fluorouracil in the gastrointestinal tract) in a molar ratio of 1: 0.4: 1. The 3-year OS was improved in the S-1 group (80.1% in S-1 group vs. 70.1% in the observation group, P = 0.003). The toxicity profile was very favorable. Although S-1 may impact the clinical practice in Asian population, the results of this agent in Western population are rather disappointing as demonstrated in the First-Line Advanced Gastric Cancer Study (FLAGS) [22••]. This may be due to biological differences between patient populations as to how the drug is metabolized.
Recently, meta-analyses of adjuvant gastric cancer trials have shown marginal benefit of adjuvant chemotherapy, with some showing a relative risk reduction of 20–28% [23–26]. In the meta-analysis by Janunger et al., although overall odds ratios (ORs) were in favor of adjuvant chemotherapy (OR = 0.84, 95% CI 0.74–0.96), when Asian studies were separated from Western studies, a survival benefit was no longer seen in Western trials (OR = 0.96, 95% CI 0.83–1.12). This may be due to the different tumor biology between Western and Eastern population. Most recently, the GASTRIC (Global Advanced/Adjuvant Stomach Tumor Research International Collaboration) Group published a large scale of meta-analysis that included recently published studies using newer agents such as epirubicin . The study which included 17 randomized trials and 3838 patients showed that adjuvant chemotherapy is associated with a statistically significant benefit on OS (hazard ratio = 0.82, 95% CI 0.75–0.9, P < 0.001).
The premise behind perioperative or preoperative chemotherapy is very similar to preoperative chemoradiation: downstage the primary tumor and eliminate micrometastases. The benefit of perioperative chemotherapy has been demonstrated in other solid tumors such as metastatic colon cancer . Similar benefit was observed in squamous cell carcinoma of the esophagus .
The most compelling evidence for perioperative chemotherapy is the phase III UK MAGIC trial . In this trial, 503 patients with potentially resectable gastric cancer were randomized to receive surgery with preoperative and postoperative ECF (epirubincin, cisplatin and 5-FU) or surgery alone. The perioperative chemotherapy group demonstrated a significantly better OS (hazard ratio = 0.75, 95% CI 0.60–0.93, P = 0.009, 5-year survival rate of 36 vs. 23%) and progression free survival (hazard ratio = 0.66, 95% CI 0.53–0.81, P < 0.001). The trial was criticized for its nonstandardized surgery, potentially inaccurate preoperative staging because of the absence of laparoscopy, and what some consider a relatively poor outcome in the surgery alone group.
Clearly, the MAGIC trial demonstrated a survival advantage of perioperative chemotherapy. This approach could be adopted in certain clinical settings. Cross-trial comparisons between the MAGIC trial and INT-0116 could potentially be misleading. For example, INT-0116 had 85% nodal positivity whereas MAGIC had only 72% nodal positivity. However, these are two distinct patient groups as many factors may influence nodal assessment such as surgical approach.
The recent large phase III preoperative chemotherapy studies, MRC OEO2 and Intergroup 8911, had completely different conclusions . However, these two study populations enrolled predominant esophageal cancer. In the OEO2 study, a total of 802 were randomized to either preoperative chemotherapy with two cycles of cisplatin and 5-FU followed by surgical resection or surgery alone. The study demonstrated a benefit of OS for the preoperative chemotherapy group with a 16% risk reduction (hazard ratio = 0.84, 95% CI 0.72–0.98, P = 0.03). However, the Intergroup 8911 did not support OS advantages.
Thus, current data do not support one approach over the other. Several currently ongoing phase III trials will address the role of chemotherapy in preoperative vs. postoperative setting (Table 1). In addition, the role of radiation in this disease will be further evaluated.
Preoperative therapy has certain potential advantages over postoperative therapy. Preoperative therapy may downstage the tumor and potentially increase the rate of resectability. Preoperative therapy may sterilize the operative field and thereby reduce the risk of tumor seeding. Furthermore, early administration of systemic chemotherapy in the preoperative setting may eliminate micrometastasis without delay. Preoperative chemoradiation also allows better radiation field design. Clinically, preoperative chemoradiation is better tolerated.
Most preoperative chemoradiation studies were conducted in esophageal cancers. Recently, a number of prospective studies have assessed the efficacy of preoperative chemoradiation in gastric cancer [31–33,34••,35]. However, most of the studies have relatively small number of patients.
Ajani et al. treated 41 patients with two cycles of 5-FU, paclitaxel and cisplatin, followed by radiotherapy with concurrent paclitaxel and infusional 5-FU, followed by surgery in 40 patients. The study showed a pathologic complete response rate (RR) of 20%, R0 resection rate of 78%, and median survival beyond 36 months. In a phase II trial conducted by the Radiation Therapy Oncology Group (RTOG), 49 patients were treated with two cycles of induction chemotherapy with 5-FU, leucovorin and cisplatin, followed by radiation therapy with concurrent 5-FU and paclitaxel, followed by surgery . Grade 4 toxicity occurred in 21% of patients. Among 43 evaluable patients, the pathologic complete RR was 27% and the R0 resection rate was 77%.
A recent randomized trial from Germany compared preoperative chemotherapy with preoperative chemoradiation [36••]. In this study, 126 patients with adenocarcinoma of the lower esophagus or gastric cardia were randomized to receive either induction chemotherapy with 5-FU, leucovorin and cisplatin, or the same chemotherapy followed by radiation therapy (30 Gy) with concurrent cisplatin and etoposide, followed by surgery in both groups. The study was closed early because of slow accrual. The pathologic complete RR was 16% in the chemoradiation group and 2% in the chemotherapy group (P = 0.03). The 3-year OS rate was higher in the chemoradiation group (47%) compared with the chemotherapy group (28%), but this difference did not reach statistical significance (P = 0.07). It should be noted that because of early closure and lower than planned accrual, this study had limited power to detect a survival difference. Additionally, the dose of radiotherapy was substantially less than in other studies, and this may have further impacted results. Although results from this trial are not definitive, this study does suggest a survival benefit trend for preoperative chemoradiation compared with preoperative chemotherapy in patients with gastroesophageal junction adenocarcinoma. A meta-analysis of four randomized trials also indicated a survival benefit with preoperative radiotherapy, compared with surgery alone .
The results of these prospective studies of preoperative chemoradiation are promising. However, randomized trials are needed to validate the benefit of preoperative chemoradiation.
Therapy for metastatic disease
Both single-agent and combination chemotherapy have been used in advanced metastatic gastric cancer. Active agents have included 5-FU, cisplatin, mitomycin C, doxorubicin, epirubicin, and etoposide, with RRs which vary from 10 to 20% [38–43]. Wagner et al. performed a meta-analysis from randomized phase II and III trials and showed that chemotherapy is better than best supportive care, combination chemotherapy with doublet is superior than single agent, and the best survival is achieved with three agents at the cost of more toxicities.
In 1985, Cullinan et al. published a study comparing the efficacy of the following three regimens: 5-FU, 5-FU plus adriamycin and FAM (5-FU, adriamycin and mitomycin C) in advanced gastric patients. Surprisingly, 5-FU plus adriamycin and FAM did not increase palliative effects in RR and survival. In contrast, 5-FU plus adriamycin and FAM added more toxicities to 5-FU. In 1997, Webb et al. reported a randomized trial comparing ECF with FAMX (5-FU, adriamycin, methotrexate) and found that ECF has better response (RR 45% for ECF vs. 21% for FAMX, P = 0.0002) and survival (median survival 8.9 months for ECF vs. 5.7 months for FAMX, P = 0.0009). These results were confirmed by studies reported from different groups [42,45]. In Europe, ECF is considered as the standard of care for metastatic gastric caner.
A recently published study, V-325 , is a large phase III trial comparing docetaxel–cisplatin–5-FU (DCF) with cisplatin–5-FU. It was demonstrated that DCF had a 32% lower risk of disease progression (hazard ratio = 1.473, 95% CI 1.189–1.825) and a 22.7% lower risk of death (hazard ratio = 1.293, 95% CI 1.041–1.606). Grade 3–4 toxicities were more frequent in the DCF group than in the cisplatin–5-FU group (81 vs. 75%). Importantly, quality of life was maintained for longer period of time with the DCF combination . However, the DCF regimen was criticized for the modest survival benefit at the cost of high toxicity, which could become a challenge in clinical practice. A recent phase II study reported by Roth et al. showed that ECF, DCF and docetaxel–cisplatin have similar RR with increasing hematological toxicities in ECF and DCF. Palliative chemotherapy in patients with metastatic gastric cancer should be individualized. For those with good performance status, both DCF and ECF are reasonable first-line therapies.
New agents such as oxaliplatin, capecitabine, and S-1 have been evaluated in treating advanced gastric cancer. Oxaliplatin-based regimens have been evaluated in phase II clinical trials and had demonstrated RRs of 38–63% with a median OS over 10 months [49–52]. Cunningham et al. further compared the efficacy among four regimens: ECF, EOX (epirubincin, oxaliplatin and capecitabine), EOF and ECX in a phase III study [Randomised multicentre phase III study comparing capecitabine with fluorouracil and oxaliplatin with cisplatin in patients with advanced oesophagogastric (OG) cancer (REAL 2)]. The study showed that EOX had superior OS (hazard ratio = 0.8, 95% CI 0.66–0.97, P = 0.02). Further analysis also demonstrated that capecitabine had modest survival benefit over 5-FU (hazard ratio = 0.86, 95% CI 0.80–0.99), whereas oxaliplatin and cisplatin are interchangeable.
Although S-1 demonstrated promising activity in Asian population [54–56], the efficacy of S-1 in Western population is rather disappointing. Three large Japanese phase III studies using either S-1 alone or in combination with other chemotherapy were reported [57–59]. Narahara et al. showed that a high RR was achieved when S-1 was combined with cisplatin (54 vs. 31%). Furthermore, the 2-year OS was improved (23.6% in S-1 + cisplatin, 15.3% in S-1, hazard ratio = 0.774, P = 0.0366). At the same time, Chin et al. compared S-1 plus irinotecan with S-1 alone. Combination of S-1 and irinotecan produced a significantly higher RR over S-1 alone (41.5% for S-1 + irinotecan vs. 26.9% for S-1 alone, P = 0.035). Following these Asian studies, FLAGS is the first phase III trial to compare the survival benefit of cisplatin/S-1 to cisplatin/5FU in Western population [22••]. However, the study did not reach its primary endpoint. S-1 did not demonstrate its superiority over 5-FU when combined with cisplatin. In the subgroup analysis, S-1 showed a survival benefit in patients with diffuse histology. Thus, a separate study is recently launched to further investigate the efficacy of S-1 in diffuse histology.
Integrating targeted agents has been extensively investigated over the past couple of years. Agents that have been evaluated in the clinic include bevacizumab, cetuximab and trastuzumab. Van Cutsem et al. presented the phase III Trastuzumab for Gastric Cancer trial at the 2009 American Society of Clinical Ontology (ASCO) annual meeting. A total of 594 patients with Her2/Neu positive metastatic or recurrent gastroesophageal cancer were randomized to receive either chemotherapy (cisplatin and capecitabine or 5FU) with trastuzumab or chemotherapy alone. The median OS was significantly improved with the addition of trastuzumab compared with chemotherapy alone: 13.5 vs. 11.1 months, respectively (hazard ratio = 0.74, 95% CI 0.60–0.91, P = 0.0048). Overall RR was 47.3% in the trastuzumab arm and 34.5% in the chemotherapy arm (P = 0.0017). Interestingly, the study also demonstrated that the efficacy of trastuzumab was directly correlated with the Her2/Neu expression measured by immunohistochemistry staining rather than fluorescent in-situ hybridization test. Currently, the agent is seeking US Food and Drug Administration (FDA) approval for gastric cancer in the United States.
The second agent that might demonstrate benefit in gastric cancer is bevacizumab. At the 2010 ASCO annual meeting, Kang et al. presented the Study of Bevacizumab in Combination With Capecitabine and Cisplatin as First-line Therapy in Patients With Advanced Gastric Cancer (AVAGAST) wherein bevacizumab was combined with standard chemotherapy. The study accrued a total of 774 patients with gastric or gastroesophageal junction cancer to receive chemotherapy with placebo or chemotherapy with bevacizumab. Although the study did not meet the primary endpoint (median OS hazard ratio = 0.87, P = 0.1002), the progression-free survival is significantly longer in the bevacizumab arm (6.7 months in bevacizumab arm vs. 5.3 months in the placebo arm, P = 0.0037). The overall RR was increased from 29.5 to 38% (P = 0.012) with the addition of bevacizumab.
The management of gastric cancer has been rapidly evolving over the past decade. Clinical data demonstrated that multidisciplinary approach is usually required to achieve maximum clinical benefit. Integrating targeted agents in gastric cancer treatment offers a new alternative to attack this disease. However, selecting patients who will benefit from the therapy remains a challenge.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 669–671).
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