Gastric Cancer: Nagoya Is Not New York
John S. Macdonald,
Aptium Oncology, Los Angeles, CA
See accompanying articles doi: 10.1200/JCO.2011.36.5908 and doi: 10.1200/JCO.2011.36.7136
Adenocarcinoma of the stomach and gastroesophageal junctionis a signiﬁcant problem worldwide, with more than 900,000 casesoccurringyearly.
Thecurative treatment of gastric cancer is based on surgical gastrectomy.However, after gastrectomy alone, relapse resulting in death frommetastatic disease is relatively common. For this reason, adjunctivetherapies to surgery have been extensively explored in clinical trialsover the last 40 years.
Some of these adjunctive therapies have beenacceptedasstandardsofcare.InNorthAmericaandwesternEurope,patients with stages II-IV (M0) disease who have undergone gastrec-tomy beneﬁt in disease-free and overall survival from postoperativechemoradiotherapy.
In patients identiﬁed preoperatively as havingresectablegastriccancer,pre-andpostoperativecytotoxicchemother-apy,
a strategy termed perioperative therapy, has been accepted as astandard of care on the basis of results from the Medical ResearchCouncil Adjuvant Gastric Infusional Chemotherapy (MAGIC) trialpublishedin2006byCunninghametal.
Manystudiesofpostopera-tive adjuvant chemotherapy
have been carried out in the UnitedStates and Europe, and none of these trials has resulted in a regimenbeingacceptedasastandardofcare.Although gastric cancer is an important cause of morbidity andmortalityintheWesternworld,morbidityanddeathfromthisdiseasearemuchmorecommoninAsia.Forexample,approximately60%of the 900,000 cases occurring worldwide are seen in east Asia.
For thisreason, there has been great interest in improving the treatment of stomach cancer in Asia. Asian surgeons have developed carefully plannedsurgicalprotocolsforgastriccancerresection,includingwell-deﬁned systematic nodal dissection (D2 nodal dissection).
Thesesurgical procedures have been thought by some to improve the curerate of stomach cancer, but when subjected to phase III trials in theWest, more extensive resection did not result in increased cure ratescompared with less radical surgery.
The larger gastric resections (D2gastrectomies) were also associated with more operative morbidity.Although cure rate was not increased with D2 nodal dissection, theprecision of staging was markedly improved
when compared withthe less rigorous nodal dissections commonly performed in theUnitedStates.
reportthe5-year results of a phase III trial of adjuvant chemotherapy in morethan1,000Japanesepatientswithresectedgastriccancer.Thisclinicaltrial, known as Adjuvant Chemotherapy Trial of TS-1 for GastricCancer (ACTS-GC), evaluated the oral ﬂuoro-pyrimidine S-1 in pa-tientswithresectedstageII/IIIstomachcancer.
Thisagenthasbeenshown to potentially improve on the efﬁcacy of oral ﬂuorinated py-rimidines by combining the antineoplastic agent with two biologicmodulatorsaimedatreducingboweltoxicityandincreasingtheanti-tumorefﬁcacyoftheﬂuoro-pyrimidine.The ACTS-GC trial enrolled 1,034 patients with stages II-IIIresected gastric carcinoma. Patients all underwent D2 gastrectomiesandthenwererandomlyallocatedto1yearofS-1therapyortosurgery alone. The results of ACTS-GC reporting 3-year survivals were ﬁrstpublished in
New England Journal of Medicine
in November 2007.
Eighty percent of S-1 patients were alive at 3 years after gastrectomy versus 70% of surgery-only patients. These survival differences werehighly statistically signiﬁcant and raised provocative questions notonlyabouttheactivityofadjuvantchemotherapyingastriccancer,butalsoaboutpotentialdifferencesbetweenstomachcancerinAsiacom-paredwiththesametumorhistologyintheWest.To Western oncologists, there are several striking ﬁndingsconcerning the ACTS-GC study and its outcomes. First, this phaseIII clinical trial is well designed and well powered. It is a prospec-tively randomized trial of oral therapy with S-1 monotherapy inpatients who underwent D2 gastrectomy versus patients who un-derwent D2 gastrectomy with no adjuvant therapy. There were1,034 patients randomly allocated on ACTS-GC, providing a sta-tistical power to easily detect clinically important differences. Thefact that monotherapy with S-1 was the treatment arm is unusualto oncologists in north America and western Europe, who gener-ally use combination chemotherapy in advanced stomach cancerand assume that an active multidrug regimen would be the mostlikely candidate for success as adjuvant therapy. The most strikingﬁnding of ACTS-GC is the survival outcome in both the treatmentand control arms. Table 1 compares the 5-year survival outcomesof the US Southwest Oncology Group Coordinated Intergrouptrial(INT0116)ofpostoperativechemoradiationandtheUKperi-operative chemotherapy trial (MAGIC) with the outcomes of ACTS-GC. As can be seen, the ACTS-GC results are strikingly better both for treatment (72% 5-year survival) and for thesurgery-onlycontrols(61%5-yearsurvival)thantheMAGICperi-operative chemotherapy results (36% and 23%, respectively) andINT0116 (43% and 28%, respectively). Western oncologists areparticularly impressed with how well the patients treated withsurgery only do. One could argue that the Japanese patients hadlower stage disease at gastrectomy and therefore had better prog-noses than the patients included in INT0116 and MAGIC. In thatregard,Table2showsthatACTS-GCpatientshadsomewhatmore
E D I T O R I A L S
© 2011 by American Society of Clinical Oncology
Journal of Clinical Oncology,
Vol 29, 2011
Copyright 2011 by American Society of Clinical Oncology
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