Chester Clinic

 

Doi:10.1016/s0140-6736(11)61873-4

Adjuvant capecitabine and oxaliplatin for gastric cancer
after D2 gastrectomy (CLASSIC): a phase 3 open-label,
randomised controlled trial
Yung-Jue Bang*, Young-Woo Kim, Han-Kwang Yang, Hyun Cheol Chung, Young-Kyu Park, Kyung Hee Lee, Keun-Wook Lee, Yong Ho Kim, Sang-Ik Noh, Jae Yong Cho, Young Jae Mok, Yeul Hong Kim, Jiafu Ji, Ta-Sen Yeh, Peter Button, Florin Sirzén, Sung Hoon Noh*, for the CLASSIC trial investigators† Summary
Background D2 gastrectomy is recommended in US and European guidelines, and is preferred in east Asia, for Published Online
patients with resectable gastric cancer. Adjuvant chemo therapy improves patient outcomes after surgery, but the DOI:10.1016/S0140-
benefi ts after a D2 resection have not been extensively investigated in large-scale trials. We investigated the eff ect on 6736(11)61873-4
disease-free survival of adjuvant chemotherapy with capecitabine plus oxaliplatin after D2 gastrectomy compared See Online/Comment
with D2 gastrectomy only in patients with stage II–IIIB gastric cancer.
Methods The capecitabine and oxaliplatin adjuvant study in stomach cancer (CLASSIC) study was an open-label, *Both authors contributed
parallel-group, phase 3, randomised controlled trial undertaken in 37 centres in South Korea, China, and Taiwan.
Patients with stage II–IIIB gastric cancer who had had curative D2 gastrectomy were randomly assigned to receive †CLASSIC trial investigators
listed at the end of Article adjuvant chemotherapy of eight 3-week cycles of oral capecitabine (1000 mg/m² twice daily on days 1 to 14 of each
Department of Internal
cycle) plus intravenous oxaliplatin (130 mg/m² on day 1 of each cycle) for 6 months or surgery only. Block Medicine (Prof Y-J Bang MD),
randomisation was done by a central interactive computerised system, stratifi ed by country and disease stage. and Department of Surgery
Patients, and investigators giving interventions, assessing outcomes, and analysing data were not masked. The (Prof H-K Yang MD), Seoul
primary endpoint was 3 year disease-free survival, analysed by intention to treat. This study reports a prespecifi ed National University College of
Medicine, Seoul, South Korea;
interim effi
cacy analysis, after which the trial was stopped after a recommendation by the data monitoring committee. Gastric Cancer Branch, Research
The trial is registered at ClinicalTrials.gov (NCT00411229).
Institute and Hospital,
National Cancer Center,
Findings 1035 patients were randomised (520 to receive chemotherapy and surgery, 515 surgery only). Median follow-up Goyang-si, Gyeonggi-do,
South Korea (Y-W Kim MD);
was 34·2 months (25·4–41·7) in the chemotherapy and surgery group and 34·3 months (25·6–41·9) in the surgery only Department of Surgery
group. 3 year disease-free survival was 74% (95% CI 69–79) in the chemotherapy and surgery group and 59% (53–64) in (Prof S H Noh MD), and
the surgery only group (hazard ratio 0·56, 95% CI 0·44–0·72; p<0·0001). Grade 3 or 4 adverse events were reported in Department of Medical
279 of 496 patients (56%) in the chemotherapy and surgery group and in 30 of 478 patients (6%) in the surgery only Oncology, Yonsei Cancer
Center, Cancer Metastasis
group. The most common adverse events in the intervention group were nausea (n=326), neutropenia (n=300), and Research Centre
decreased appetite (n=294).
(Prof H C Chung MD,
Prof J Y Cho MD), Yonsei
Interpretation Adjuvant capecitabine plus oxaliplatin treatment after curative D2 gastrectomy should be considered as a University College of Medicine,
Seoul, South Korea;
treatment option for patients with operable gastric cancer.
Department of Surgery,
Chonnam National University
Funding F Hoff mann-La Roche and Sanofi -Aventis.
Hwasun Hospital, Jeonnam,
South Korea (Prof Y-K Park MD);
Yeungnam University College
Adjuvant chemotherapy is a standard component of of Medicine, Daegu, South
Gastric cancer is the second most common cause of resectable gastric cancer therapy and improves patient Korea (Prof K H Lee MD);
cancer-related mortality worldwide, with 988 000 new outcomes,12,13 although the preferred treatment diff ers Department of Internal
Medicine, Seoul National
cases and 736 000 deaths per year.1 Surgery is the main by geographical region. The recommended adjuvant University Bundang Hospital,
treatment for operable gastric cancer; however, recurrence treatment is chemoradiotherapy in the USA,11 peri- Seongnam, Gyeonggi-do,
rates are high (about 40–80% in advanced cases).2,3 In east operative chemotherapy in the UK and parts of Europe,10 South Korea (Prof K-W Lee MD);
Asia, particularly in Japan and South Korea, D2 gastrectomy and adjuvant chemotherapy in Japan.4 These recom- Department of Surgery, Kyung
Hee University School of
is the standard surgical treatment for localised gastric mendations are based on the US Intergroup-011614 and Medicine, Seoul, South Korea
cancer.4,5 In Europe, two randomised controlled studies UK Medical Research Council Adjuvant Gastric Infusional (Prof Yo H Kim MD);
done in the UK6 and the Netherlands7 showed little initial Chemotherapy (MAGIC)15 trials, which showed survival Department of Surgery, Seoul
diff erence between D1 and D2 surgery. However, long-
ts with postoperative chemoradio therapy and Veterans Hospital, Seoul,
South Korea (S-I Noh MD);
term follow-up of the Dutch trial showed a reduction in perioperative chemotherapy, respectively, compared with Department of Surgery
gastric cancer-specifi c deaths with extended surgery,8 a surgery alone. However, the benefi ts were evident only (Prof Y J Mok MD) and,
fi nding that has been supported by fi ndings from a smaller after limited dissection of regional lymph nodes in both Department of Internal
Taiwanese study.9 As a result of these fi ndings, D2 studies, raising questions about the need for postoperative Medicine (Prof Ye H Kim MD),
Korea University College of
gastrectomy is now recommended in European10 and US radiotherapy or perioperative chemotherapy after D2 Medicine, Seoul, South Korea;
treatment guidelines11 for resectable disease.
gastrectomy.16,17 The Japanese recommendation for www.thelancet.com Published online January 7, 2012 DOI:10.1016/S0140-6736(11)61873-4
Beijing Cancer Hospital,
adjuvant therapy is based on the Adjuvant Chemotherapy and achieved R0 resection. Patients were included only if Beijing, China (Prof J Ji MD);
Trial of TS-1 for Gastric Cancer (ACTS-GC) study,13,18 they had a Karnofsky performance status of 70% or more. Department of Surgery, Chang
which showed a survival benefi t with adjuvant Patients who had had chemotherapy, immunotherapy, or Gung Memorial Hospital at
Linkou, Taipei, Taiwan
chemotherapy after D2 gastrectomy compared with radio therapy for gastric cancer were excluded. Patients (Prof T-S Yeh MD); Infopeople,
surgery alone. A subgroup analysis of the data showed a had to have adequate renal function (creatinine clearance Sydney, NSW, Australia
survival benefi t for stages II and IIIA disease.
>50 mL/min or serum creatinine ≤1·5 times the upper (P Button MSc); and
Increased acceptance of D2 gastrectomy raises new limit of normal [ULN]), hepatic function (total bilirubin F Hoff mann-La Roche, Basel,
Switzerland (F Sirzén MD)
questions about the optimum adjuvant therapy for ≤1·5 times the ULN, aspartate or alanine aminotransferase Correspondence to: patients with operable gastric cancer. The Capecitabine ≤2·5 times the ULN, alkaline phosphatase ≤2·5 times the Prof Yung-Jue Bang, Department and Oxaliplatin Adjuvant Study in Stomach Cancer ULN), and haematological function (absolute neutrophil of Internal Medicine, Seoul (CLASSIC) study was designed to compare the eff ect count ≥1·5×10⁹/L or platelet count ≥100×10⁹/L).
National University College of of adjuvant capecitabine plus oxaliplatin after D2 The protocol was approved by the institutional review Medicine, Jongno-gu, Seoul 110 744, South Korea gastrectomy with surgery alone on disease-free survival board at each participating institution, and the study was in patients with stage II or III gastric cancer. Although done in accordance with the Declaration of Helsinki and
several phase 2 trials have shown the activity of the Good Clinical Practice Guidelines defi ned by the
capecitabine and oxaliplatin in advanced gastric International Conference on Harmonization. All patients
cancer,19–22 phase 3 data for this regimen in gastric provided written, informed consent.
cancer are absent. We summarise the results of the
prespecifi ed interim analysis from the CLASSIC study, Randomisation and masking
which was done after a recommendation by the Patients were randomly assigned to receive capecitabine
independent data monitoring committee to fully assess
and oxaliplatin or surgery alone in a 1:1 ratio. Random- and report the study.
isation was done after surgery with a centralised interactive computerised system and stratifi ed by country and disease stage (II, IIIA, and IIIB). A random permuted block design Study design and patients
(with a block size of four) was used in each combination CLASSIC was a randomised, open-label, multicentre, of country and stage of disease stratum. Because study parallel-group, phase 3 study. The trial was done in centre was not a stratifi cation factor, a particular study 37 centres in South Korea, China, and Taiwan.
centre could not predict the next allocation, or even know Eligible patients were ambulatory; aged 18 years or how many numbers in the block had already being older; had histologically confi rmed, American Joint allocated if they had correctly guessed the block size. Committee on Cancer/Union Internationale Contre le Patients, and investigators giving inter ventions, assessing Cancer23 stage II (T2N1, T1N2, T3N0), IIIA (T3N1, T2N2, outcomes, and analysing data were not masked.
T4N0), or IIIB (T3N2) gastric adenocarcinoma with no See Online for webappendix
evidence of metastatic disease; and had had D2 surgery Procedures
All patients had curative D2 gastrectomy within 6 weeks before randomisation. At least 15 lymph nodes were examined to ensure adequate disease classifi cation. All surgeons had experience doing this type of surgery (>50 procedures per year). To further ensure the quality of surgery, standard operating procedures were predefi ned 515 received surgery only 520 received capecitabine and given to all surgeons before the start of the study, and surgery was photographed.
Patients assigned to the chemotherapy group received eight 3-week cycles of oral capecitabine (1000 mg/m² 86 did not complete 174 did not complete twice daily on days 1–14 of each cycle) plus intravenous observation phase observation phase oxaliplatin (130 mg/m² on day 1 of each cycle). Dose reductions or interruptions were allowed to manage potentially serious or life-threatening adverse events. Subsequent dose escalations for capecitabine were allowed after two more cycles in the absence of grade 2–4 toxic eff ects, if oxaliplatin was permanently discontinued. For toxic eff ects judged to be due to only one drug, the dose of the other drug was not modifi ed. In cases of oxaliplatin-related neurological adverse events, capecitabine could be continued as monotherapy. Figure 1: Trial profi le
Oxaliplatin monotherapy was not allowed if capecitabine Numbers of patients eligible not available. Reasons for withdrawal during the study treatment or observation phase are given in the webappendix.
was discontinued.
www.thelancet.com Published online January 7, 2012 DOI:10.1016/S0140-6736(11)61873-4
Prespecifi ed tumour assessments to assess whether This Article reports a planned interim analysis of data, patients were disease free were done by abdominal CT or which was triggered because the necessary number of MRI every 6 months during the fi rst 3 years and yearly events had occurred. The trial was then stopped after a thereafter, and by chest radiograph every 3 months for recommendation by the independent data monitoring the fi rst 2 years, every 6 months for the subsequent year, committee, who reviewed the data in March, 2011.
and yearly thereafter. If signs or symptoms indicated a The trial was registered at ClinicalTrials.gov possible recurrence or development of a new gastric (NCT00411229).
cancer, investigations were then done to verify whether
the patient was disease free. The same assessment was Role of the funding source
used for each patient.
The study sponsor helped to design the study, to interpret Adverse events were graded according to the National data, and helped with the decision to submit the report Cancer Institute's Common Terminology Criteria for for publication in conjunction with the authors.
Adverse Events (version 3.0). Adverse events were Employees of the sponsor collected, managed, and
documented during chemotherapy and for 28 days after analysed data. The sponsors funded writing assistance.
the last dose of study medication. In the surgery only The two principal investigators (Y-JB and SHN) had full
group, adverse events were recorded for up to 190 days access to all study data and had fi nal responsibility for
after randomisation. Relative dose intensity was defi ned the decision to submit for publication.
as the dose received divided by the planned dose for the
eight treatment cycles.
Surgery only (n=515)
Capecitabine and oxaliplatin
The primary endpoint was 3 year disease-free survival, defi ned as the time from randomisation to the time of recurrence of the original gastric cancer, development of a new gastric cancer, or death from any cause. Karnofsky performance status (%) Secondary endpoints were overall survival (defi ned as the time from the date of randomisation to date of death Body surface area (m²) from any cause) and safety (any adverse event).
Time since surgery (months) AJCC/UICC23 stage 3 year disease-free survival in the oxaliplatin and capecitabine and surgery only groups was predicted to be 65·0% and 56·2%, respectively (hazard ratio [HR] 0·75, with the assumption of a 3 year dropout rate of 10% with recruitment for 12 months). The null hypothesis (no diff erence in 3 year disease-free survival between study groups) was tested with Cox proportional hazards regression stratifi ed by country and disease stage, with covariates of age, sex, and nodal metastatic status. A sample size of 512 patients in each group was planned to record 385 disease-free survival events with 80% power at a 0·05 signifi cance level by a two-sided log-rank test.
cacy analysis was scheduled for after 257 events (66·8% of the number of events at fi nal analysis), with stopping boundaries decided by application of the Lan-DeMets method24 and O'Brien- Fleming α spending function25 using the actual number of events. Interim effi cacy analyses for disease-free survival and overall survival were done with Cox proportional hazards regression by intention to treat. All effi Lymph nodes examined analyses were repeated per protocol to test the sensitivity of the results (data not shown). Safety was assessed per Time to event endpoints were analysed with Kaplan- Meier survival methods. Estimates of treatment eff ect Data are mean (SD), n (%), or median (IQR). Intention-to-treat population; all patients were Asian. were calculated as HRs with 95% CIs. Study treatment AJCC/UICC=American Joint Cancer Committee/Union Internationale Contre le Cancer. *Antrum is the lower third, groups were compared with a two-sided log-rank test. body the middle third, and fundus the upper third. †Includes multiple localisations. We also did a prespecifi ed analysis of disease-free Table 1: Baseline patient characteristics
survival in subgroups.
www.thelancet.com Published online January 7, 2012 DOI:10.1016/S0140-6736(11)61873-4
gastric cancer, or died, compared with 163 patients (32%) in the surgery only group. 3 year disease-free survival was Capecitabine and oxaliplatin higher in the chemotherapy group than in the surgery only group (HR 0·56, 95% CI 0·44–0·72; p<0·0001). 3 year disease-free survival was 74% (95% CI 69–79) in the chemotherapy group and 59% (53–64) in the surgery only group. Kaplan-Meier curves for disease-free survival show early separation between the two study groups (fi gure 2A).
65 patients (13%) died in the chemotherapy group compared with 85 (17%) in the surgery only group. 3 year overall survival was 83% (95% CI 79–87) in the chemotherapy group and 78% (74–83) in the surgery only group (HR 0·72, 95% CI 0·52–1·00; p=0·0493; fi gure 2B), although a robust estimate of median overall survival is not yet available.
In the chemotherapy group, 96 patients (18%) developed Number at risk
Surgery only 515 442 415 388 353 332 289 255 211 188 148 120 58 recurrences or new occurrences of gastric cancer Capecitabine 520 462 442 425 409 379 332 295 246 218 166 147 compared with 155 patients (30%) in the surgery only group. The sites of gastric cancer recurrence or new occurrence were the peritoneum (47 in the chemotherapy group vs 56 in the surgery only group), locoregional sites (21 vs 44), and distant sites (49 vs 78).
Subgroup analysis of 3-year disease-free survival showed consistent benefi t for oxaliplatin and capecitabine compared with surgery only for several factors (fi gure 3). Survival was signifi cantly higher in the chemotherapy group than in the surgery only group for all disease stages (fi gure 3). 3 year disease-free survival for stage II disease was 85% (95% CI 79–90) for chemotherapy and 71% (64–78) for surgery alone, for stage IIIa disease 66% (57–75) for chemotherapy and 51% (42–60) for surgery alone, and for stage IIIb disease 61% (48–73) for chemotherapy and 33% (95% CI 15%–51%) for surgery alone.
For nodal status 1 and 2 subgroups 3 year disease-free survival was signifi cantly improved with oxaliplatin and Number at risk
capecitabine compared with surgery only, but not for Surgery only 515 473 460 453 443 424 380 338 288 238 204 156 112 nodal status 0 (fi gure 3).
Capecitabine 520 481 468 461 451 425 396 352 306 255 217 169 120 39 Of the 1035 randomised patients, 61 were excluded from the safety population (25 in the chemotherapy Figure 2: 3 year disease-free survival (A) and preliminary overall survival (B) in the intention-to-treat population
group vs 36 in the surgery only group). The main reasons for exclusion were absence of follow-up information (18 vs 36) and not receiving study treatment after Figure 1 shows the trial profi le. Between June, 2006, and randomisation (22 in the chemotherapy group). Addition- June, 2009, 1035 patients were randomly assigned to ally, one patient in the surgery only group received receive either oxaliplatin and capecitabine (n=520) or chemotherapy in error, and was included in the surgery only (n=515; intention-to-treat population). The chemotherapy group for the safety analysis. The safety trial was stopped because accrual was complete and the population included 496 patients in the chemotherapy necessary 257 disease-free survival events had occurred. group and 478 patients in the surgery only group.
The median duration of follow-up was 34·2 months 346 patients (67%) assigned to the chemotherapy group (25·4–41·7) in the chemotherapy group and 34·3 months received eight cycles as planned. 167 patients had (25·6–41·9) in the surgery only group; 468 patients were capecitabine dose reductions, 147 had cycle interruptions, followed up in the chemotherapy group and 463 in the and 369 had cycle delays, and 163 patients needed surgery only group. Patient demographic and baseline oxaliplatin dose reductions. The median relative dose disease characteristics were similar in each group intensity was 85% for capecitabine and 98% for (table 1).
At the cutoff for the interim analysis, 106 patients (20%) Table 2 shows adverse events reported by 10% or in the chemotherapy group had relapsed, developed a new more of patients. Almost nine times as many grade 3 or www.thelancet.com Published online January 7, 2012 DOI:10.1016/S0140-6736(11)61873-4
4 adverse events were reported in the chemotherapy HR (95% CI)
group than in the surgery group. The most commonly reported adverse events at any grade in the chemotherapy group were nausea, neutropenia, decreased appetite, 0·66 (0·33–1·32) peripheral neuropathy, diarrhoea, and vomiting (table 2). 0·56 (0·43–0·73) The most common grade 3 or 4 adverse events in Stage of disease
the chemotherapy group were neutropenia, thrombo- 0·55 (0·36–0·84) cytopenia, nausea, and vomiting (table 2). Grade 3 or 0·57 (0·39–0·82) 4 peripheral neuropathy, a cumulative toxic eff ect 0·57 (0·35–0·95) associated with oxaliplatin, occurred in 12 (2%) patients. 43 patients (9%) had serious adverse events related to Age (years)
chemotherapy. Two patients died within 28 days of the 0·62 (0·47–0·83) last dose of treatment in the chemotherapy group: one 0·48 (0·30–0·78) because of sepsis (possibly related to treatment), and one because of metastatic gastric cancer (judged unrelated to the study treatment). One patient in the surgery only 0·83 (0·54–1·27) group died because of cardiac failure during the 0·49 (0·36–0·66) observation phase.
Nodal status
Adverse events led to chemotherapy dose modifi cations 0·90 (0·41–1·97) in 446 (90%) patients; neutropenia, nausea, vomiting, 0·62 (0·44–0·89) thrombocytopenia, and decreased appetite were the 0·45 (0·31–0·66) most common reasons (webappendix). Discontinuations because of adverse events in the chemotherapy group Weight (kg)
occurred in 50 (10%) patients, mainly as a result of 0·63 (0·46–0·88) neutropenia (n=17; 3%), thrombocytopenia (n=5; 1%), 0·52 (0·36–0·75) and vomiting (n=5; 1%).
This study shows that a 6 month course of chemotherapy Favours capecitabine and oxaliplatin Favours surgery only after D2 gastrectomy improves 3 year disease-free survival
compared with surgery only. Chemotherapy reduced the Figure 3: 3 year disease-free survival by stratifi cation and prognostic factors in the intention-to-treat population
relative risk of disease recurrence, new disease
occurrence, or death compared with surgery alone.
Moreover, a subgroup analysis suggested that adjuvant
Surgery alone (n=478)
Capecitabine and oxaliplatin
capecitabine and oxaliplatin was benefi cial for all disease stages (II, IIIA or IIIB). The overall survival data from our study are not yet mature; however, the data suggest Patients with ≥1 adverse event an improvement in overall survival with capecitabine and oxaliplatin compared with surgery only. An analysis after a median follow-up of 5 years is planned to conclusively Decreased appetite establish the overall survival benefi t of capecitabine and Peripheral neuropathy oxaliplatin in this setting.
We used 3 year disease-free survival as the primary endpoint because most relapses occur within 3 years of surgery.26 Although 3 year disease-free survival has not yet been formally validated as a surrogate measure, Hand–foot syndrome preliminary data from the Global Advanced/Adjuvant Stomach Tumor Research International Collaboration (GASTRIC) group indicate that 3 year disease-free survival is strongly correlated with 5 year overall survival, the benchmark for judging eff ectiveness of adjuvant therapy in gastric cancer.27 The clinical relevance of disease-free survival in gastric cancer is supported by the GASTRIC Peripheral sensory neuropathy group meta-analysis of 17 trials, which showed an 18% relative risk reduction for both disease-free survival and Data are n (%). *Patients who received at least one dose of capecitabine or oxaliplatin.
overall survival with adjuvant chemotherapy compared Table 2: Adverse events reported by ≥10% of patients (safety population*)
with surgery only in patients with resectable disease.12 www.thelancet.com Published online January 7, 2012 DOI:10.1016/S0140-6736(11)61873-4
Before CLASSIC, the Japanese ACTS-GC trial was the are to other regions where disease management practices only large randomised trial of adjuvant chemotherapy might diff er. The CLASSIC trial had good patient (1 year of the oral fl uoropyrimidine S-1) after curative outcomes; the 3 year overall survival rate in the surgery resection with D2 gastrectomy.13 Our fi ndings accord only group was substantially higher than that in the US with the ACTS-GC trial, and together these studies show Intergroup-0116 and UK MAGIC populations (78% in that adjuvant chemotherapy after D2 gastrectomy CLASSIC vs 30–40% in Intergroup-0116 and MAGIC).14,15 improves outcomes in patients with resectable gastric Although our patient population had fewer T3 and cancer (panel).
T4 lesions than did US and European gastric cancer We used surgery only as the reference treatment for populations (44% in CLASSIC vs 68% in Intergroup-0116 our trial because it was the appropriate choice when the vs 64% in MAGIC),14,15 node-positive disease was more CLASSIC trial was designed. At that time, no large-scale frequent (90% vs 85% vs 72%).14,15 The diff erence in randomised trials supporting the use of adjuvant therapy outcomes seems unlikely to be due to prognostic after D2 surgery had been done. The fi ndings of the disparities, although the possibility of intrinsic biological ACTS-GC trial,13 which established fl uoropyrimidine diff erences in gastric cancer by region has been monotherapy as an eff ective adjuvant regimen after D2 suggested.30 Instead, we suggest that the favourable surgery, were reported in 2007, after recruitment for the outcomes in our study are a result of the consistent use of CLASSIC trial had begun. Both postoperative chemo- D2 surgery and the high quality of that surgery (ensured radiotherapy and perioperative chemotherapy have been by prospectively defi ned standard operating procedures adopted as standard treatments in the USA and Europe, and sampling of at least 15 lymph nodes). Now that D2 but their relevance after D2 surgery is unknown.
gastrectomy is standard of care in both Europe10 and the The frequency, severity, and type of adverse events USA,11 our study fi ndings could be highly relevant for, and documented with capecitabine and oxaliplatin in the might be generalisable to, other regions when D2 surgery CLASSIC study were consistent with the safety profi le is done by experienced surgeons.
reported with adjuvant capecitabine and oxaliplatin On the basis of our fi ndings, we suggest that a trial of in colon cancer.28,29 In our study more than half of patients capecitabine and oxaliplatin plus trastuzumab after D2 who received chemotherapy had peripheral neuropathy—a gastrectomy in patients with human epidermal growth cumulative, dose-related toxic eff ect associated with factor receptor (HER)-2-positive operable disease is oxaliplatin—although grade 3 or 4 events were infrequent. warranted. Such a study would build on the ToGA trial,31 Most patients needed dose modifi cations because of which showed improved overall survival with trastuzumab adverse events, the most common being neutropenia, plus chemotherapy in patients with HER-2-positive nausea, and vomiting. Capecitabine, should be started at advanced disease.
the recommended dose with prompt dose modifi cations In conclusion, fi ndings from the CLASSIC trial support as needed for emergent adverse events.
the use of adjuvant capecitabine and oxaliplatin as a new A key question about our trial, as with any trial done in treatment option for patients with resectable disease.
one geographical region, is how generalisable the fi ndings Contributors
All authors had access to all the study data, analysed data, interpreted data, and reviewed, edited and approved the report for publication. Y-JB Panel: Research in context
and SHN designed the study. Y-JB, Y-WK, H-KY, HCC, Y-KP, KHL, K-WL, YHK, S-IN, JYC, YJM, YHK, JFJ, T-SY, and SHN recruited patients and collected data. PB undertook the statistical analysis.
A meta-analysis from the GASTRIC group based on individual patient data from CLASSIC trial investigators
17 randomised clinical trials12 showed that adjuvant chemotherapy with a fl uorouracil-based Y I Park (National Cancer Center, Goyang, South Korea); Y-J Bang regimen improves overall survival and disease-free survival compared with surgery only. (Seoul National University College of Medicine, Seoul, South Korea); However, the type of gastrectomy used in the studies was not standardised. D2 gastrectomy H C Chung, J Y Cho (Yonsei Cancer Center, Younsei University College of Medicine, Seoul, South Korea); Y-K Park (Chonnam National is now recommended in US11 and European10 treatment guidelines, and is widely used in east University Hwasun Hospital, Jeonnam, South Korea); K H Lee Asia as the preferred type of surgery for patients with operable gastric cancer. However, the (Yeungnam University College of Medicine, Daegu, South Korea); benefi ts of adjuvant chemotherapy after this more extensive type of resection were K W Lee (Seoul National University Bundang Hospital, Seongnam, uncertain. To address this question, two phase 3 trials were initiated (ACTS-GC and CLASSIC). South Korea); S Y Kim (Kyung Hee University Hospital, Seoul, South Korea); S I Noh (Veterans Health Service Medical Center, Seoul, South The ACTS-GC trial showed a survival benefi t with adjuvant fl uoropyrimidine monotherapy Korea); Y J Mok, Y H Kim (Korea University College of Medicine, Seoul, after D2 gastrectomy compared with surgery only.13 South Korea); J-H Choi (Ajou University Hospital, Suwon, South Korea); H-M Chin (St Vincent's Hospital, Suwon, South Korea); W Yu (Kyungpook National University Hospital, Daegu, South Korea); J-I Lee The CLASSIC trial shows that adjuvant therapy with capecitabine and oxaliplatin improves (Korea Cancer Center Hospital, Seoul, South Korea); D-B Shin (Gachon 3 year disease-free survival after D2 gastrectomy compared with D2 gastrectomy only. University Gil Hospital, Incheon, South Korea); H S Park (Soonchunhyang University Hospital, Seoul, South Korea); H S Song Improved overall survival was also evident after only 3 years, although the data are (Keimyung University Hospital Dongsan Medical Center, Daegu, South immature and patient follow-up is ongoing. Together, the ACTS-GC and CLASSIC trials Korea); D H Yang (Chonbuk National University Hospital, Jeonju, South show that fl uoropyrimidine-based adjuvant therapy improves outcomes after D2 Korea); S H Lee (Kosin University Gospel Hospital, Busan, South gastrectomy in patients with operable gastric cancer.
Korea); S N Lee (Ewha Womans University School of Medicine, Seoul, South Korea); JF Ji (Beijing Cancer Hospital, Beijing, China); L Han www.thelancet.com Published online January 7, 2012 DOI:10.1016/S0140-6736(11)61873-4
(Tianjin Medical University Cancer Institute and Hospital, Tianjin, 12 Paoletti X, Oba K, Burzykowski T, et al, and the GASTRIC (Global China); Y Zhan (Sun Yat-Sen University Cancer Center, Guangzhou, Advanced/Adjuvant Stomach Tumor Research International Guangdong, China); Y L He (The First Affi liated Hospital, Sun Yat-Sen Collaboration) Group. Benefi t of adjuvant chemotherapy for University, Guangzhou, Guangdong, China); Y P Liu (First Clinical resectable gastric cancer: a meta-analysis. JAMA 2010; 303: 1729–37.
College of China Medical University, Shenyang, Liaoning, China); 13 Sakuramoto S, Sasako M, Yamaguchi T, et al, and the ACTS-GC S Wang (Peking University People's Hospital, Beijing, China); Group. Adjuvant chemotherapy for gastric cancer with S-1, an oral C M Huang (Fujian Medical University Union Hospital, Fujian, China); fl uoropyrimidine. N Engl J Med 2007; 357: 1810–20.
Y H Sun (Zhongshan Hospital, Fudan University, Shanghai, China); 14 Macdonald JS, Smalley SR, Benedetti J, et al. Chemoradiotherapy M Yan (Rudin Hospital, Shanghai Jiao Tong University School of after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 2001; Medicine, Shanghai, China); Y Q Shi (Fudan University Shanghai Cancer Center, Shanghai, China); T-S Yeh (Chang Gung Memorial 15 Cunningham D, Allum WH, Stenning SP, et al, and the MAGIC Trial Hospital, Taoyuan, Taiwan); P-H Lee (National Taiwan University Participants. Perioperative chemotherapy versus surgery alone for Hospital, Taipei, Taiwan); C-S Chang (Changhua Christian Hospital, resectable gastroesophageal cancer. N Engl J Med 2006; 355: 11–20.
Changhua, Taiwan); P-W Lin (National Cheng Kung University 16 Ohtsu A, Sasako M. Overview of adjuvant therapy for resected Hospital, Tainan, Taiwan); R-K Hsieh (Mackay Memorial Hospital, gastric cancer: diff erences in Japan and the United States. Taipei, Taiwan); and S-Y Chen (Veterans General Hospital, Cancer Semin Oncol 2005; 32 (suppl 9): S101–04.
Center, Taipei, Taiwan).
17 Ohtsu A, Yoshida S, Saijo N. Disparities in gastric cancer Confl icts of interest
chemotherapy between the East and West. J Clin Oncol 2006; PB was employed by Roche Products Australia at the time of the study and is currently employed by Infopeople. FS is employed by 18 Sasako M, Sakuramoto S, Katai H, et al. Five-year outcomes of a F Hoff mann-La Roche and owns stock in the company. Y-JB has acted as randomized phase III trial comparing adjuvant chemotherapy with S-1 versus surgery alone in stage II or III gastric cancer. J Clin Oncol a consultant for F Hoff mann-La Roche and Sanofi -Aventis, and has 2011; 29: 4387–93.
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11 NCCN. NCCN Clinical Practice Guidelines in Oncology. Gastric Cancer. Version 2.2011. 2011; http://www.nccn.org (accessed Dec 5, 2011). www.thelancet.com Published online January 7, 2012 DOI:10.1016/S0140-6736(11)61873-4

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