Gastric cancer (GC) is a major health burden throughout the world, especially in certain endemic regions. GC is commonly diagnosed at an advanced stage because of the lack of early detection strategies and is usually associated with a dismal outcome. For patients with localized GC (LGC), surgery is the best cure: cure rates are highly associated with the surgical pathology stage. Adjunctive therapies improve the cure rates by about an additional 10%. Therefore, a multimodality approach is highly recommended for all patients with LGC. This article highlights some of the therapeutic advances made against GC and features important ongoing trials.
Key points
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Gastric cancer (GC) is the fourth most common cancer in men and the fifth most common cancer in women worldwide.
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Surgery is the key for curing patients with localized GC. However, surgery alone is insufficient to achieve the highest possible cure rate, which can be obtained by the addition of adjunctive therapies.
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Advanced GC is an incurable condition; however, it is now possible to prolong survival with oncologic therapies.
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Patients with advanced GC with Her2-neu protein overexpression can benefit from the addition of trastuzumab to combination chemotherapy.
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Improved therapy will likely result from a better understanding of the molecular pathways in GC.
Introduction
GC is frequently diagnosed in the advanced stage and is associated with a poor prognosis. The incidence of GC still remains high, and there are many endemic areas in the world. Annually, the estimated number of new GC cases worldwide is 640,600 for men and 349,000 for women. In 2012, approximately 21,320 new cases were likely to be diagnosed and 10,540 patients were expected to die in the United States. Localized GC (LGC) is a potentially curable condition, and surgery plays a major role in the achievement of cure. The cure rates from surgery vary considerably with regions but are predominantly based on the surgical stage of LGC; however, surgical technique and surgical volume (of a center and surgeon) highly contribute to the cure rates (as well as the rates of complications and mortality). Advanced GC (AGC) is a treatable but not curable condition. AGC and LGC are highly heterogeneous (driven by patient and tumor genetic differences). In this regard, discovery of tumor subsets defined by their molecular subtypes (eg, Her2-neu overexpressing tumors vs those that do not overexpress Her2-neu) is likely to drive the direction of future research and to set the stage for improved and individualized therapies. This review highlights the current therapeutic strategies for LGC and AGC.
Introduction
GC is frequently diagnosed in the advanced stage and is associated with a poor prognosis. The incidence of GC still remains high, and there are many endemic areas in the world. Annually, the estimated number of new GC cases worldwide is 640,600 for men and 349,000 for women. In 2012, approximately 21,320 new cases were likely to be diagnosed and 10,540 patients were expected to die in the United States. Localized GC (LGC) is a potentially curable condition, and surgery plays a major role in the achievement of cure. The cure rates from surgery vary considerably with regions but are predominantly based on the surgical stage of LGC; however, surgical technique and surgical volume (of a center and surgeon) highly contribute to the cure rates (as well as the rates of complications and mortality). Advanced GC (AGC) is a treatable but not curable condition. AGC and LGC are highly heterogeneous (driven by patient and tumor genetic differences). In this regard, discovery of tumor subsets defined by their molecular subtypes (eg, Her2-neu overexpressing tumors vs those that do not overexpress Her2-neu) is likely to drive the direction of future research and to set the stage for improved and individualized therapies. This review highlights the current therapeutic strategies for LGC and AGC.
Localized gastric cancer (LGC)
Baseline clinical stage should be established meticulously. Although baseline clinical stage is not as highly associated with long-term outcome as the surgical pathology stage, the baseline clinical stage does help to define the short-term therapeutic strategy. It is important to emphasize that physician(s) from one discipline (eg, a gastroenterologist or a surgeon) should not decide the initial therapeutic strategy of LGC but that a consensus decision, derived from a multidisciplinary discussion of the baseline staging of patients with LGC, should be reached because this is likely to provide the highest benefit to a patient.
Once it is established that the patient has LGC, the therapeutic plan should include adjunctive strategy for most patients (an example of an exception would be an LGC <3 cm in diameter and ≤T1bN0). The preferred adjunctive strategy differs by region worldwide, reflecting differences in practice patterns. The extent of lymphadenopathy also varies, and it is usually suboptimal in most areas of the world where GC is not highly prevalent. Surgery remains the best contributor to the cure rate, and when surgery is not done or not possible, one can anticipate a dismal outcome. In the following section we discuss adjunctive strategies.
Adjunctive strategies
Postoperative Adjuvant Chemoradiation
The most important study that established this strategy firmly in the West is the Intergroup 0116 trial, headed by the Southwest Oncology Group. This trial was based on prior nonrandomized observations in patients with LGC who received chemoradiation therapy. This trial was a phase 3 study that compared observation after surgery (control) with chemoradiation adjuvant after following surgery (experimental arm).
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Recruitment duration: 1991–1998
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Total number of patients enrolled: 603
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Number of eligible patients: 559
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Criteria for eligibility: R0 resection for LGC (clinical stage ranged from IA to IV [but M0])
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High-risk LGC; 85% patients had lymph node metastases and more than 65% had a T3 primary
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Of the 559 patients, 282 were randomized to the experimental arm and 227 were randomized to the control arm
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The cure rate was significantly higher in the experimental arm (median 36 vs 27 months, P = .005) and included improved local control (30 vs 19 months, P = .001)
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Inadequate surgery (54% having a D0 nodal dissection) reflected the standard of surgery at the community level in the United States at that time
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Results have prevailed after more than 10 years of follow-up
Three other relevant studies are worth mentioning. The CALGB-driven intergroup adjuvant trial did not take advantage of improving chemoradiation efforts and instead compared fluorouracil to the combination of epirubicin/cisplatin/fluorouracil and demonstrated no advantage with the latter. The second study was a retrospective comparison of 2 patient populations (one group had surgery and the other had surgery plus chemoradiation), and this comparison demonstrated benefit for the chemoradiation group. However, the use of a retrospective design greatly limits this conclusion. The third study was a prospective comparison in patients with LGC who had an excellent D2 dissection (median number of nodes evaluated was >30). In this ARTIST trial (Adjuvant Chemoradiation Therapy in Stomach Cancer), both group of patients were treated after surgery (chemotherapy vs chemoradiation). The primary analysis of this study demonstrated no benefit for the group that received chemoradiation; however, an unplanned subgroup analysis (an ad hoc strategy that is generally questionable and often considered unreliable) demonstrated benefit for node-positive patients. The ARTIST trial therefore casts doubt on the benefit from chemoradiation when high-quality surgery is performed.
Postoperative Chemotherapy
In the West, where surgery is often suboptimal, trials have not shown a significant benefit for adjuvant chemotherapy. In addition to having inadequate surgery, most studies in the West have been underpowered and suboptimally conceived and/or executed.
In Southeast Asia, where the GC surgical standards are usually excellent, 2 prospective randomized well-conceived and well-executed trials have demonstrated benefit from adjuvant chemotherapy. The ACTS-GC trial (Adjuvant Chemotherapy Trial of TS-1 for Gastric Cancer) was conducted in 1059 Japanese patients with LGC, and patients were randomized to 1 year of an oral fluoropyrimidine, S-1, or observation only. The primary analysis demonstrated a 33% improvement in overall survival for the S-1 group. In addition, these results held up with longer follow-up. The CLASSIC trial (Capecitabine and Oxaliplatin Adjuvant Study in Stomach Cancer) randomized 1035 patients with LGC to capecitabine plus cisplatin as adjuvant for 6 months follow-up after surgery and demonstrated 44% improvement in disease-free survival (its primary end point) for the chemotherapy group versus the group that underwent surgery only. Overall survival data are still pending.
Although meta-analyses have demonstrated some benefit for systemic adjuvant chemotherapy, they do not establish a standard of care and are limited by multiple design weaknesses.
Perioperative or Preoperative Chemotherapy
The MAGIC (Medical Research Council Adjuvant Gastric Infusional Chemotherapy) trial established the evidence for the use of perioperative (or preoperative) chemotherapy over surgery alone in the West.
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Total number of patients randomized: 504
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Eligibility: R0 resection of LGC or gastroesophageal junction adenocarcinoma (15%) patients
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Experimental arm: epirubicin, cisplatin, and fluorouracil before and after surgery
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Control arm: follow-up after surgery
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Results: a 25% reduction in risk of death and 13% improvement in 5-year survival rates (hazard ratio = 1.31, 95% confidence interval = 1.08–1.61)
This trial had several limitations including inadequate staging, poor surgical technique, and poor outcome of the control group. Also, it confirmed previous findings that this group of patients cannot tolerate postoperative combination chemotherapy.
A second trial of preoperative chemotherapy was terminated prematurely because of poor accrual. This French trial (ACCORD07-FFCD 9703) had relatively few (25%) patients with LGC, and it randomized patients to cisplatin/fluorouracil versus observation after surgery. Even with a small sample size, patients who had chemotherapy benefited.
Whether a preoperative treatment strategy is applicable to patients with LGC who have excellent surgery is the subject of the PRODIGY (Docetaxel+Oxaliplatin+S-1 [DOS] Regimen as Neoadjuvant Chemotherapy in Advanced Gastric Cancer) trial (preoperative docetaxel, oxaliplatin, and S-1 followed by postoperative S-1 vs postoperative S-1 for patients with D2 resection; NCT01515748 ; also see Table 1 ).
| Trial | Intervention | Primary Outcome, Enrollment | Estimated Start Date–End Date | Location (Countries) |
|---|---|---|---|---|
| CRITICS study NCT00407186 | Chemoradiotherapy(45 Gy in 5 wk with daily CDDP and XELODA) after preoperative chemotherapy (3x ECC) and adequate (D1+) surgery vs postoperative chemotherapy (3x ECC) | OS 788 | December 2006–June 2013 | Netherlands |
| NCT01512745 | Oral apatinib vs placebo | PFS, OS 270 | January 2011–June 2012 | China |
| NCT01671449 | SC vs SOX | PFS 338 | December 2012–December 2015 | Republic of Korea |
| NCT01099085 | XELODA/CDDP + simvastatin vs XELODA/CDDP + placebo | PFS 244 | February 2009–May 2013 | Republic of Korea |
| NCT01534546 | Perioperative SOX vs SOX or XELOX as postoperative chemotherapy | 3-yr DFS 1059 | March 2012–September 2014 | China |
| Japan Clinical Oncology Group Study (JCOG 0501) NCT00252161 | Surgery vs neoadjuvant chemotherapy (TS-1 + CDDP) + surgery | OS 316 | November 2005–April 2015 | Japan |
| NCT01711242 | XELOX vs XELOX + radiotherapy | 3-yr DFS 300 | January 2012–December 2015 | China |
| NCT01470742 | XELOX vs XELODA | OS 200 | September 2010–??? | Republic of Korea |
| PRODIGY trial NCT01515748 | DOS + surgery + S-1 vs surgery + adjuvant S-1 | 3-yr PFS 640 | January 2012–December 2017 | Republic of Korea |
| NCT01248403 | Paclitaxel + placebo vs paclitaxel + RAD001 | OS 500 | October 2011–January 2016 | Germany |
| NCT01283217 | DS vs SP | 3-yr DFS 166 | March 2010–March 2016 | Republic of Korea |
| NCT01468389 | Taxanes or platinum in combination with XELODA vs chemotherapy followed by XELODA alone | PFS 300 | Nov 2011–January 2013 | China |
| NCT01285557 | S-1/CDDP vs fluorouracil/CDDP | OS 500 | February 2011–June 2014 | Multinational; United States and others |
| NCT01662869 | Drug: onartuzumab Drug: placebo Drug: FOLFOX6 | OS 800 | November 2012–February 2016 | Multinational |
| NCT01697072 | Drug: rilotumumab Other: placebo | OS 450 | October 2012–December 2015 | United States, Australia, Canada |
| NCT01641939 | Trastuzumab emtansine vs taxane | OS 412 | September 2012–September 2015 | Multinational |
| NCT00450203 | ECX + bevacizumab vs ECX | Safety, efficacy, OS 1100 | October 2007–December 2014 | United Kingdom |
| NCT01516944 | Perop S-1 + oxaliplatin vs XELOX | DFS 729 | February 2012–December 2015 | China |
| NCT01523015 | Preoperative chemotherapy- and chemoradiotherapy followed by surgery vs surgery | Pathologic response to treatment 100 | January 2012–December 2015 | Poland |
| NCT01450696 | Drug: trastuzumab [Herceptin] Drug: XELODA Drug: CDDP | OS 400 | December 2011–June 2020 | multinational |
| NCT01748851 | XELOX vs FOLFOX | PFS 438 | December 2012–December 2015 | Republic of Korea |
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