Phase III Trial Comparing Capecitabine Plus Cisplatin ...

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Phase III Trial Comparing Capecitabine Plus Cisplatin Versus Capecitabine Plus Cisplatin With Concurrent Capecitabine Radiotherapy in Completely Resected Gastric Cancer With D2 Lymph Node Dissection: The ARTIST Trial Jeeyun Lee, Do Hoon Lim, Sung Kim, Se Hoon Park, Joon Oh Park, Young Suk Park, Ho Yeong Lim, Min Gew Choi, Tae Sung Sohn, Jae Hyung Noh, Jae Moon Bae, Yong Chan Ahn, Insuk Sohn, Sin Ho Jung, Cheol Keun Park, Kyoung-Mee Kim, and Won Ki Kang Jeeyun Lee, Do Hoon Lim, Sung Kim, Se Hoon Park, Joon Oh Park, Young Suk Park, Ho Yeong Lim, Min Gew Choi, Tae Sung Sohn, Jae Hyung Noh, Jae Moon Bae, Yong Chan Ahn, Cheol Keun Park, Kyoung-Mee Kim, and Won Ki Kang, Samsung Medical Center, Sungkyunkwan University School of Medicine; Insuk Sohn and Sin Ho Jung, Samsung Cancer Research Institute, Seoul, Korea; and Sin Ho Jung, Duke University, Durham, NC. Submitted September 1, 2011; accepted October 24, 2011; published online ahead of print at www.jco.org on December 19, 2011. Supported in part by F. Hoffmann-La Roche through donation of capecitabine. J.L., D.H.L., and S.K. contributed equally to this work. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article. Clinical Trials repository link available on JCO.org. Corresponding author: Won Ki Kang, MD, PhD, Division of HematologyOncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong Kangnam-gu, Seoul 135-710 Korea; e-mail: wkkang@skku .edu. © 2011 by American Society of Clinical Oncology 0732-183X/12/3003-268/$20.00 DOI: 10.1200/JCO.2011.39.1953

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Purpose The ARTIST (Adjuvant Chemoradiation Therapy in Stomach Cancer) trial was the first study to our knowledge to investigate the role of postoperative chemoradiotherapy therapy in patients with curatively resected gastric cancer with D2 lymph node dissection. This trial was designed to compare postoperative treatment with capecitabine plus cisplatin (XP) versus XP plus radiotherapy with capecitabine (XP/XRT/XP). Patients and Methods The XP arm received six cycles of XP (capecitabine 2,000 mg/m2 per day on days 1 to 14 and cisplatin 60 mg/m2 on day 1, repeated every 3 weeks) chemotherapy. The XP/XRT/XP arm received two cycles of XP followed by 45-Gy XRT (capecitabine 1,650 mg/m2 per day for 5 weeks) and two cycles of XP. Results Of 458 patients, 228 were randomly assigned to the XP arm and 230 to the XP/XRT/XP arm. Treatment was completed as planned by 75.4% of patients (172 of 228) in the XP arm and 81.7% (188 of 230) in the XP/XRT/XP arm. Overall, the addition of XRT to XP chemotherapy did not significantly prolong disease-free survival (DFS; P ⫽ .0862). However, in the subgroup of patients with pathologic lymph node metastasis at the time of surgery (n ⫽ 396), patients randomly assigned to the XP/XRT/XP arm experienced superior DFS when compared with those who received XP alone (P ⫽ .0365), and the statistical significance was retained at multivariate analysis (estimated hazard ratio, 0.6865; 95% CI, 0.4735 to 0.9952; P ⫽ .0471). Conclusion The addition of XRT to XP chemotherapy did not significantly reduce recurrence after curative resection and D2 lymph node dissection in gastric cancer. A subsequent trial (ARTIST-II) in patients with lymph node–positive gastric cancer is planned. J Clin Oncol 30:268-273. © 2011 by American Society of Clinical Oncology

INTRODUCTION

Gastric cancer is the second most common cause of cancer-related death worldwide.1,2 A high rate of locoregional as well as distant recurrence has been reported after surgical resection with curative intent in gastric cancer.3-5 Numerous meta-analyses have suggested a survival benefit associated with adjuvant chemotherapy in patients with gastric cancer.6-9 However, despite wide acceptance of the benefits of adjuvant therapy, there is no currently recognized standard regimen, particularly in countries where D2 resection is a routine surgical procedure. Because of the high incidence of locoregional recur-

rence after surgery, local radiotherapy (RT) has emerged as a strong candidate for use in combination with adjuvant chemotherapy.10 The INT-0116 (Intergroup 0116) study, the largest phase III trial to compare chemoradiotherapy (CRT) versus observation, demonstrated a definite survival benefit with CRT in patients with gastric cancer, with 3-year overall survival rates of 50% and 41% for the postoperatively treated and surgery-alone groups, respectively.10 However, the major limitation for global acceptance of the INT0116 regimen as an adjuvant treatment modality in gastric cancer has been the limited lymph node dissection (D0 or D1) performed in 90% of patients

© 2011 by American Society of Clinical Oncology

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Adjuvant Chemoradiation Therapy in Gastric Cancer

enrolled onto the trial. Although the superiority of D2 lymph node dissection in reducing locoregional relapse has not been consistently demonstrated when compared with D1 dissection,11,12 the survival benefit from postoperative CRT needs to be evaluated in patients with gastric cancer who have undergone extended D2 lymph node dissection,13 because this is the most widely accepted surgical procedure in Asian and European countries. The potential beneficial effect of adjuvant CRT was observed in our recent retrospective study, which demonstrated prolonged survival and decreased recurrence rates in patients with gastric cancer after D2 resection with the addition of postoperative CRT (5-year overall survival rates of 57% and 51% for CRT v no CRT, respectively).14 The ARTIST (Adjuvant Chemoradiation Therapy in Stomach Cancer) trial is the first study to our knowledge to investigate the efficacy of postoperative CRT as adjuvant treatment in patients with gastric cancer with curative resection and extended D2 lymph node dissection. The capecitabine plus cisplatin (XP) regimen is one of the current standards of care in Asia for patients with metastatic, unresectable gastric cancer,15 and the tolerability and efficacy of capecitabine combined with RT (XRT) have previously been demonstrated in rectal cancer.16 Thus, we designed this study to compare six cycles of XP chemotherapy with two cycles of XP followed by concurrent XRT followed by two additional cycles of XP in patients with gastric cancer after D2 dissection. PATIENTS AND METHODS This study was conducted in accordance with the Declaration of Helsinki and all of its amendments. The study was approved by the institutional review

board at Samsung Medical Center, and all patients provided written informed consent before study enrollment. The trial was registered at clinicaltrials.gov. Eligibility Criteria Patients were recruited to the study based on the following eligibility criteria: histologically confirmed adenocarcinoma of the stomach; surgical resection of tumor without residual disease (R0 gastrectomy); D2 lymph node dissection; age 18 years or older; Eastern Cooperative Oncology Group performance status of 0 or 1; adequate function of major organs (including cardiac, hepatic, and renal function); and adequate bone marrow function (hemoglobin ⬎ 10g/dL; absolute neutrophil count [ANC] ⱖ 1,500/␮L; platelet count ⱖ 100,000/␮L). Patients with coexisting malignancies or who were unable to tolerate chemotherapy because of other systemic illnesses were excluded from the study. Patients with stage IA or IB (T2aN0) disease (according to the American Joint Committee on Cancer 2002 staging system), microscopically positive resection margin, and involvement of M1 lymph node or distant metastases were excluded from the study. Patients who had undergone gastrectomy with D1 lymph node dissection were also excluded. Surgery The surgical requirement for eligibility was curative, with en bloc resection of the tumor with disease-negative margins. All patients had undergone extensive (ⱖ D2) lymph node dissection. This procedure entails resection of all perigastric lymph nodes and celiac, splenic or splenic-hilar, hepatic arterial, and cardial lymph nodes, depending on the location of the primary tumor. Study Design and Treatment Eligible patients were randomly assigned to receive adjuvant XP or XP/ XRT/XP. Stratification factors were disease stage and type of surgery (subtotal v total gastrectomy). In the chemotherapy arm, patients received six cycles of the XP regimen (capecitabine 1,000 mg/m2 twice daily on days 1 to 14; cisplatin 60 mg/m2 on day 1 every 3 weeks). Patients assigned to the XP/ XRT/XP arm received two cycles of XP (capecitabine 1,000 mg/m2 twice daily on days 1 to 14; cisplatin 60 mg/m2 on day 1 every 3 weeks), then XRT (45 Gy of radiation at 1.8 Gy per day, 5 days per week, for 5 weeks with continuous

Enrolled (N = 458)

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Randomly assigned (n = 228)

Randomly assigned (n = 230)

XP arm (n = 226) Refused before treatment (n = 2)

XP/XRT/XP arm (n = 227) Refused before treatment (n = 3)

Discontinued Refused treatment Documented recurrence Adverse events Others

Discontinued during XP#1-2 (n = 24) Refused treatment (n = 17) Adverse events (n = 3) Others (n = 4) Discontinued during XRT (n = 3) Adverse events (n = 2) Refused treatment (n = 1) Discontinued during XP#3-4 (n = 12) Adverse events (n = 7) Disease recurrence (n = 2) Refused treatment (n = 2) Others (n = 1)

(n = 54) (n = 20) (n = 4) (n = 20) (n = 10)

Completed planned treatment (n = 172)

Completed planned treatment (n = 188)

Final analysis (n = 228)

Final analysis (n = 230)

Fig 1. CONSORT diagram. XP, capecitabine plus cisplatin; XRT, radiotherapy with capecitabine.



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capecitabine 825 mg/m2 twice daily during radiotherapy), followed by two additional cycles of XP (capecitabine 1,000 mg/m2 twice daily on days 1 to 14; cisplatin 60 mg/m2 on day 1 every 3 weeks). RT was targeted to the tumor bed, anastomosis site, duodenal stump, regional lymph nodes, and 2 cm beyond the proximal and distal margins of resection. The remnant stomach was not routinely included within the radiation field. Other than for T4 lesions, the tumor bed was not the RT target, because there was no microscopic residuum after R0 gastrectomy. Anteriorposterior parallel opposing fields were used for RT, and the RT dose was 45 Gy, with 1.8-Gy daily fractions administered over 5 weeks. Dose Modification Administration of XP chemotherapy was delayed for 1 week if neutropenia with an ANC of less than 1,500/␮L or thrombocytopenia with a platelet count less than 75,000/␮L occurred. If the ANC was 1,500/␮L or greater and platelet count was 75,000/␮L or greater after a 1-week delay, chemotherapy was administered without dose reductions. If the ANC was less than 1,000/␮L or platelet count was less than 75,000/␮L after a 1-week delay, chemotherapy was delayed for 1 additional week. If the ANC was from 1,000 to 1,500/␮L or greater and platelet count was 75,000/␮L or greater after a 1-week delay from the planned date of chemotherapy, the dose of capecitabine was reduced by 25%. If patients required a delay of longer than 3 weeks for recovery, treatment was discontinued, and these patients were treated outside the study. If grade 3 or greater nausea occurred despite adequate administration of antiemetic drugs, the dose of cisplatin was reduced by 25% of the planned dose. For grade 2 or greater nonhematologic toxicities, chemotherapy was delayed until the patient’s symptoms were reduced to grade 1. For cases of grade 2 hand-foot syndrome (HFS), the capecitabine dose was reduced by 25%. In cases of grade 3 HFS, capecitabine was reduced by 50% of the starting dose. Toxicity was assessed using the Common Terminology Criteria for Adverse Events v. 2.0 and was evaluated during every treatment cycle (every 3 weeks during RT). Statistical Considerations The primary end point of the ARTIST study was disease-free survival (DFS), with overall survival, recurrence rate, and toxicity as key secondary end points. Assuming a 15% dropout rate, 4 years of accrual, and an additional 3 years of follow-up, a total of 448 patients (224 per arm) provided 80% power to detect hazard rates of 0.2310 for the XP arm and 0.1593 for the XP/XRT/XP arm (hazard ratio[HR],1.450)bythelog-ranktest,withatwo-sided ␣ of0.05.Thefinalanalysis was scheduled for when 227 events (recurrences or deaths) were observed, but this data analysis was performed at only 127 events, because fewer adverse events than expected were observed, probably because of accrual of more patients with earlystage (stage Ib/II) disease than expected. DFS was defined as the time from surgery to recurrence, second primary cancer (other than basal cell carcinoma of skin, papillary thyroid cancer, or cervix cancer in situ), or death, whichever occurred first. The log-rank test was used for univariate analysis, and Cox’s regression was used for multivariate analysis. All P values are two sided.

Table 1. Patient Demographics and Clinical Characteristics XP Arm (n ⫽ 228) Characteristic Age, years Median Range Sex Male Female ECOG performance status 0 1 Primary tumor site Proximal Body Antrum Multiple/diffuse Primary tumor classification stageⴱ IB II IIIA IIIB IV (M0) Regional lymph nodes classificationⴱ N0 N1 N2 N3 No. of lymph nodes dissected Median Range No. of involved lymph nodes Median Range Lauren classification Intestinal Diffuse Mixed Not specified

No.

%

XP/XRT/XP Arm (n ⫽ 230) No.

56 22-77

% 56 28-76

153 75

67.1 32.9

143 87

62.2 37.8

96 132

42.1 57.9

99 131

43.0 57.0

9 112 87 20

3.9 49.1 38.2 8.8

13 107 90 20

5.7 46.5 39.1 8.7

50 86 48 17 27

21.9 37.7 21.1 7.5 11.8

49 84 53 18 26

21.3 36.5 23.0 7.8 11.3

35 123 52 18

15.4 53.9 22.8 7.9

27 130 49 24

11.7 56.5 21.3 10.4

40 13-142

40 12-84

3 0-50

3 0-51

88 130 6 4

38.6 57.0 2.6 1.8

75 144 8 3

32.6 62.6 3.5 1.3

Abbreviations: ECOG, Eastern Cooperative Oncology Group; XP, capecitabine plus cisplatin; XRT, radiotherapy with capecitabine. ⴱ American Joint Committee on Cancer Staging System, 6th edition (2002).

RESULTS

Study Population Between November 2004 and April 2008, 458 patients were recruited to the study. Patient disposition throughout the study is shown in Figure 1. Patient baseline characteristics were well balanced between the treatment groups (Table 1). Treatment Delivery All patients received curative resection for gastric cancer with extended lymph node dissection. Treatment was completed as planned by 75.4%ofpatients(172of228)intheXParmand81.7%(188of230)inthe XP/XRT/XP arm (Appendix Table A1, online only). The percentage of planned doses of XP administered was 90% or greater across treatment groups. Of 230 patients randomly assigned to the XP/XRT/XP arm, 227 were treated with two cycles of XP. Subsequently, 203 patients entered the 270


XRT therapy phase. A total of 24 patients did not enter the XRT phase for the following reasons: patient refusal of RT (n ⫽ 17), patient refusal because of toxicities including nausea (n ⫽ 3), and other causes including follow-up loss (n ⫽ 4). Only three of the 203 patients who entered XRT failed to complete the 5-week course for the following reasons: myocardial infarction (n ⫽ 1), anastomosis site stenosis (n ⫽ 1), and patient refusal of further RT during treatment (n ⫽ 1). Of 200 patients who completed XRT, 188 patients completed two additional cycles of XP chemotherapy. Safety The most common nonhematologic grade 3 to 4 adverse events were vomiting, stomatitis, HFS, and diarrhea, each of which occurred in 1% to 12% of patients in both arms. Grade 4 neutropenia occurred in5.7%ofpatientsintheXParmand4.8%intheXP/XRT/XParm.Grade JOURNAL OF CLINICAL ONCOLOGY



Table 2. Toxicity Profile (all grades) XP Arm (n ⫽ 226) Grade 1

Grade 2

XP/XRT/XP Arm (n ⫽ 227)

Grade 3

Grade 4

Grade 1

Grade 2

Grade 3

Grade 4

Toxicity

No.

%

No.

%

No.

%

No.

%

No.

%

No.

%

No.

%

No.

%

Nausea Vomiting Diarrhea Stomatitis Constipation HFS Anemia Neutropenia Thrombocytopenia

114 57 83 60 85 94 124 28 30

50.4 25.2 36.7 26.5 37.6 41.6 54.9 12.4 13.3

63 19 16 11 7 26 64 78 4

27.9 8.4 7.1 4.9 3.1 11.5 28.3 34.5 1.8

28 8 4 3 2 5 3 79 0

12.4 3.5 1.8 1.3 0.9 2.2 1.3 35.0 0.0

0 0 1 0 0 — 1 13 0

0.0 0.0 0.4 0.0 0.0 — 0.4 5.7 0.0

132 75 86 50 94 88 109 21 49

58.1 33.0 37.9 22.0 41.4 38.7 48.0 9.3 21.6

43 11 14 3 6 17 80 76 24

18.9 4.8 6.1 1.3 2.6 7.4 35.2 33.5 10.6

28 7 2 4 2 7 1 99 2

12.3 3.1 0.9 1.8 0.9 3.1 0.4 43.6 0.9

0 0 0 0 0 — 0 11 0

0.0 0.0 0.0 0.0 0.0 — 0.0 4.8 0.0

Abbreviations: HFS, hand-foot syndrome; XP, capecitabine plus cisplatin; XRT, radiotherapy with capecitabine.

3 neutropenia occurred in 35.0% of patients in the XP arm and 43.6% in the XP/XRT/XP arm (Table 2). Grade 2 to 3 HFS occurred in 13.7% of all patients treated with XP and 10.6% of those treated with XP/XRT/XP. Few patients experienced grade 3 HFS (2.2% in XP arm and 3.1% in XP/XRT/XP arm; Table 2). Two treatment-related deaths were recorded during the study. One patient died as a result of neutropenic septic shock during XP chemotherapy, and one patient died as a result of non-neutropenic pneumonia in the XP/XRT/XP treatment group. Adverse events that led to treatment modifications (delays or dose reductions) occurred in 52% of patients (119 of 228) in the XP arm and 35% (80 of 230) in the XP/XRT/XP arm. The most frequent adverse event requiring treatment modification was neutropenia (58 patients in XP arm and 41 in XP/XRT/XP arm). After dose modification, including delays, the majority of occurrences of grade 3 or 4 neutropenia spontaneously recovered without granulocyte macrophage colony-stimulating factor support or complications from infections. The incidence of postoperative complications such as ileus did not increase after adjuvant therapy (Appendix Table A2, online only). Efficacy After a median follow-up duration of 53.2 months (36.9 to 77.3 months), 127 recurrence events occurred (72 in XP arm and 55 in XP/XRT/XP arm). The estimated 3-year DFS rates were 78.2% in the XP/XRT/XP arm and 74.2% in the XP arm (P ⫽ .0862; Figs 2A, 2B). In a subgroup analysis of 396 patients with positive pathologic lymph nodes, there was a statistically significant prolongation in DFS in the XP/XRT/XP arm (estimated 3-year DFS rate of 77.5%) when compared with the XP-alone arm (3-year DFS, 72.3%; P ⫽ .0365; Fig 2). In a multivariate analysis with stage and treatment arm (XP v XP/XRT/ XP; Fig 3), the addition of XRT to XP demonstrated significantly prolonged DFS, with an HR of 0.6865 (95% CI, 0.4735 to 0.9952; P ⫽ .0471). Only 108 patients had died at the time of analysis; therefore, the secondary end point of overall survival was not analyzed. Pattern of Recurrence Locoregional recurrence was defined as recurrence at the anastomosis site, duodenal stump, tumor bed, or remnant stomach or at the regional lymph nodes within the radiation field. Distant metastasis was defined as lymph node recurrence outside the radiation field, peritoneal seeding, liver metastasis, or metastasis of other extra-abdominal sites. There were no significant differences in the percentage of locoregional www.jco.org

recurrence (8.3% in XP arm v 4.8% in XP/XRT/XP arm; P ⫽ .3533) or distant metastases (24.6% in XP arm v 20.4% in XP/XRT/XP arm; P ⫽ .5568) between treatment arms (Table 3). DISCUSSION

Overall, this study demonstrated that postoperative XP with or without concurrent RT was well tolerated in the adjuvant treatment of gastric cancer. Rates of compliance were high throughout the study, and treatment was completed as planned by 75% of patients (172 of 228) in the XP armand82%(188of230)intheXP/XRT/XParm.Thiswas greater than the completion rate of only 64% observed in the INT-0116 trial, in which patients were treated with fluorouracil (FU) and leucovorin plus RT.10 In addition, rates of grade 3 to 4 adverse events observed in the present study were low in both treatment groups. Therefore, postoperative XP chemotherapy alone or with concurrent RT was feasible in patients with gastric cancer after D2 resection. Overall, there was no significant difference in DFS with the addition of XRT to XP chemotherapy after D2 resection in the postoperative setting. The benefit of adjuvant RT has long been debated in D2 resected gastric cancer based on the hypothesis that D2 resection alone may be sufficient to control locoregional recurrence. Several retrospective studies including ours have assessed the feasibility and efficacy of adjuvant CRT in D2 resected gastric cancer (approximately 20 to 990 patients).14,17,18 One prospective study comparing adjuvant CRT with FU and cisplatin versus chemotherapy in D2 resected gastric cancer was terminated early because of poor patient accrual (n ⫽ 61); no significant difference in DFS was reported.19 Thus, the reported clinical studies have all been based on limited numbers of patients. To our knowledge, the ARTIST trial is the only clinical study to date to have investigated the role of postoperative CRT in patients after curatively resected gastric cancer and extended D2 lymph node dissection. In addition, this is the first clinical trial to incorporate one of the most frequently used palliative chemotherapy regimens (ie, XP) for the treatment of gastric cancer in Asian patients. Capecitabine-based CRT has been shown to be well tolerated and capable of inducing positive tumor responses in both upper GI and rectal cancers.20,21 To date, XP is one of the most widely used chemotherapy regimens for first-line palliative care in countries where gastric cancer is prevalent. Therefore, investigation of XP chemotherapy in © 2011 by American Society of Clinical Oncology


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A

1.0

Disease-Free Survival


1.0

0.8

0.6

0.4

0.2

XP/XRT/XP XP

0.8

0.6

0.4

0.2 Treatment Stage

P = .0862

0

12

24

36

48

60

XP/XRT/XP, stage IB/II XP, stage IB/II XP/XRT/XP, stage III/IV XP, stage III/IV

0

72

Hazard ratio 95% CI P 0.686 (0.473 to 0.995) .0471 3.596 (2.380 to 5.435) < .001

12

24

B

12 21 15

24 44 39

36 49 56

48 53 67

Treatment Stage XP/XRT/XP IB+II XP/XRT/XP III+IV XP IB+II XP III+IV

60 55 70


1.0

60

72

# N events 106 11 97 38 101 20 92 46

12 2 17 3 11

24 10 32 9 28

36 10 35 15 36

48 10 37 19 43

60 11 38 19 45

Fig 3. Disease-free survival according to stage (multivariate analysis). XP, capecitabine plus cisplatin; XRT, radiotherapy with capecitabine.

0.8

0.6

0.4

0.2

XP/XRT/XP XP P = .0365

0

12

24

36

48

60

72

Time (months) # Treatment N event XP/XRT/XP 203 49 XP 193 66

12 19 14

24 42 37

36 45 51

48 47 62

60 49 65

Fig 2. Disease-free survival in (A) all patients and (B) lymph node–positive patients. XP, capecitabine plus cisplatin; XRT, radiotherapy with capecitabine.

the adjuvant setting is clinically important. Given the documented safety and efficacy profile of concurrent CRT with capecitabine, we added capecitabine at the dose of 825 mg/m2 twice daily combined with 45 Gy in 25 fractions. Collectively, the full course of XP chemotherapy and XRT was well tolerated, with low dropout rates and a high percentage of patients completing treatment. HFS is a manageable adverse effect associated with capecitabine treatment, and rates of grade 3 HFS were low in both treatment groups. Grade 2 to 3 HFS was more frequently observed in patients continuously treated with six cycles of XP compared with those treated with two cycles of XP followed by XRT and two cycles of XP. A plausible explanation for this observation is the lower dose of capecitabine therapy (825 mg/m2 twice daily) administered during RT. However, the incidence of grade 3 HFS (2.2%) in the XP group of the ARTIST trial was similar to that observed in patients receiving XP in a previous phase III trial of FU and leucovorin plus cisplatin versus XP (4%).15 The frequency of grade 3 to 4 neutropenia observed among patients treated with postoperative XP (47%) was greater than that observed in the phase III trial of FU and leucovorin plus cisplatin versus XP (16%) in the metastatic setting.15 Despite the different rates 272

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Time (months)

Time (months) # Treatment N event XP/XRT/XP 230 55 XP 228 72

36


of neutropenia between these trials, the rate of febrile neutropenia was low in both arms of the ARTIST study (⬍ 1%). Although there is still a lack of consensus regarding the standard approach to treating curatively resected gastric cancer, especially in countries where D2 resection is the standard surgical procedure, evidence suggests that postoperative chemotherapy22 or perioperative chemotherapy does confer a survival benefit after surgery.23 The CRITICS (Chemoradiotherapy After Induction Chemotherapy of Cancer in the Stomach) trial (NCT00407186) is currently investigating perioperative treatment with epirubicin, cisplatin, and capecitabine chemotherapy alone versus epirubicin, cisplatin, and capecitabine chemotherapy followed by CRT (45 Gy over 5 weeks with weekly cisplatin and daily capecitabine) in patients with gastric cancer after D1 or greater resection. The phase III CLASSIC (Capecitabine and Oxaliplatin Adjuvant Study in Stomach Cancer) trial assessed postoperative capecitabine plus oxaliplatin with observation alone after D2 resection in gastric cancer.24 Interim results showed that this regimen significantly improved 3-year DFS (P ⬍ .001; HR, 0.56; 95% CI, 0.44 to 0.72). There was a trend toward improved overall survival (P ⫽ .0775; HR, 0.74; 95% CI, 0.53 to 1.03), and there were no new or unexpected safety signals. These results reinforce the

Table 3. Pattern of Recurrence Pattern of Recurrenceⴱ Locoregional recurrence† Distant metastasis‡

XP Arm 19 56

8.3 24.6

XP/XRT/XP Arm 11 47

4.8 20.4

P .3533 .5568

Abbreviations: XP, capecitabine plus cisplatin; XRT, radiotherapy with capecitabine. ⴱ Because proportion of patients had both locoregional and distant relpases, total number of relapses is greater than number of patients who experienced relapse. †Anastomosis site, abdominal lymph node within radiotherapy field. ‡Lymph nodes outside radiotherapy field, peritoneal seeding, extraabdominal metastases.

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clinical activity of capecitabine-based adjuvant therapy and provide further justification to continue research in this area. The main weakness of the ARTIST trial is that the planned events were not reached after median follow-up duration of 53.2 months (range, 36.9 to 77.3 months). This may have been because of the fact that approximately 60% of the patients in each arm had stages IB and II disease and therefore had a better prognosis than later-stage patients. With the current rate of events, it is estimated that approximately 8 years of additional follow-up time after the completion of accrual is needed. We did not compare the two arms when deciding to make this analysis the final one. The decision was based only on the following observations: first, too many good risk patients; second, too few events at the time of final analysis by calendar; and third, too long of a required follow-up period for the planned number of events. Although there was no significant difference in DFS between the two treatment arms (P ⫽ .0862; Fig 2A), there was a statistically significant prolongation in the XP/ XRT/XP arm in positive pathologic lymph node gastric cancer after D2 lymph node dissection (P ⫽ .0365; Fig 2B). In multivariate analysis, XP/XRT/XP demonstrated significantly prolonged DFS after adjustment for stage (stages IB and II v III and IV; P ⫽ .0471; HR, 0.6865; 95% CI, 0.4735 to 0.9952; Fig 3) in the lymph node– positive subgroup. Because these findings were from a subgroup analysis, the data should be interpreted with caution. A subsequent phase III trial (ARTIST-II) to compare chemotherapy versus chemotherapy with RT in patients with D2 lymph node dissection and REFERENCES 1. Kelley JR, Duggan JM: Gastric cancer epidemiology and risk factors. J Clin Epidemiol 56:1-9, 2003 2. Kamangar F, Dores GM, Anderson WF: Patterns of cancer incidence, mortality, and prevalence across five continents: Defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol 24:2137-2150, 2006 3. Yoo CH, Noh SH, Shin DW, et al: Recurrence following curative resection for gastric carcinoma. Br J Surg 87:236-242, 2000 4. Landry J, Tepper JE, Wood WC, et al: Patterns of failure following curative resection of gastric carcinoma. Int J Radiat Oncol Biol Phys 19:13571362, 1990 5. Lim DH, Kim DY, Kang MK, et al: Patterns of failure in gastric carcinoma after D2 gastrectomy and chemoradiotherapy: A radiation oncologist’s view. Br J Cancer 91:11-17, 2004 6. Janunger KG, Hafstro¨m L, Glimelius B: Chemotherapy in gastric cancer: A review and updated meta-analysis. Eur J Surg 168:597-608, 2002 7. Panzini I, Gianni L, Fattori PP, et al: Adjuvant chemotherapy in gastric cancer: A meta-analysis of randomized trials and a comparison with previous metaanalyses. Tumori 88:21-27, 2002 8. Mari E, Floriani I, Tinazzi A, et al: Efficacy of adjuvant chemotherapy after curative resection for gastric cancer: A meta-analysis of published randomised trials—A study of the GISCAD (Gruppo Italiano per lo Studio dei Carcinomi dell’Apparato Digerente). Ann Oncol 11:837-843, 2000

pathologic lymph node–positive disease is planned to confirm the benefit of adjuvant CRT. Postoperative CRT did not improve DFS in patients with D2 resected gastric cancer with statistical significance. The postoperative XP regimen was well tolerated, and the safety data presented here are comparable to those observed in a previous study of the XP regimen in patients with advanced gastric cancer. Patients in the ARTIST trial will continue to be observed for recurrence and survival. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.

AUTHOR CONTRIBUTIONS Conception and design: Jeeyun Lee, Do Hoon Lim, Sung Kim, Won Ki Kang Provision of study materials or patients: Do Hoon Lim, Sung Kim, Se Hoon Park, Joon Oh Park, Young Suk Park, Ho Yeong Lim, Min Gew Choi, Tae Sung Sohn, Jae Hyung Noh, Yong Chan Ahn, Kyoung-Mee Kim, Won Ki Kang Collection and assembly of data: Jeeyun Lee, Se Hoon Park, Joon Oh Park, Young Suk Park, Ho Yeong Lim, Min Gew Choi, Tae Sung Sohn, Jae Hyung Noh, Jae Moon Bae, Yong Chan Ahn, Cheol Keun Park, Kyoung-Mee Kim, Won Ki Kang Data analysis and interpretation: Jeeyun Lee, Do Hoon Lim, Insuk Sohn, Sin-Ho Jung, Won Ki Kang Manuscript writing: All authors Final approval of manuscript: All authors

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