Modern Oncological Approache s to Gastric Adenocarcinoma




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








  • Gastric cancer (GC) is the fourth most common cancer in men and the fifth most common cancer in women worldwide.



  • 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.



  • Advanced GC is an incurable condition; however, it is now possible to prolong survival with oncologic therapies.



  • Patients with advanced GC with Her2-neu protein overexpression can benefit from the addition of trastuzumab to combination chemotherapy.



  • 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).







  • Recruitment duration: 1991–1998



  • Total number of patients enrolled: 603



  • Number of eligible patients: 559



  • Criteria for eligibility: R0 resection for LGC (clinical stage ranged from IA to IV [but M0])



  • High-risk LGC; 85% patients had lymph node metastases and more than 65% had a T3 primary



  • Of the 559 patients, 282 were randomized to the experimental arm and 227 were randomized to the control arm



  • 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)



  • Inadequate surgery (54% having a D0 nodal dissection) reflected the standard of surgery at the community level in the United States at that time



  • Results have prevailed after more than 10 years of follow-up



Key points about the INT0116 trial


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.







  • Total number of patients randomized: 504



  • Eligibility: R0 resection of LGC or gastroesophageal junction adenocarcinoma (15%) patients



  • Experimental arm: epirubicin, cisplatin, and fluorouracil before and after surgery



  • Control arm: follow-up after surgery



  • 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)



Key points about the MAGIC trial


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 ).



Table 1

Ongoing Phase 3 Clinical Trials for Gastric Cancer








































































































































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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Feb 26, 2017 | Posted by in GASTROENTEROLOGY | Comments Off on Modern Oncological Approache s to Gastric Adenocarcinoma
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