Clinical Investigation: Gastrointestinal Cancer
Postoperative Chemotherapy Followed by Conformal Concomitant Chemoradiotherapy in High-Risk
Gastric Cancer
Laurent Quero, M.D., M.Sc., * Zineb Bouchbika, M.D., * Honorine Kouto, M.D., M.Sc., * Valerie Baruch-Hennequin, M.D.,* Jean-Marc Gornet, M.D.,
yNicolas Munoz, M.D.,
zIsabelle Cojean-Zelek, M.D.,
xRemi Houdart, M.D.,
kYves Panis, M.D., Ph.D.,
{Patrice Valleur, M.D.,
#Thomas Aparicio, M.D., Ph.D.,** Claude Maylin, M.D.,*
and Christophe Hennequin, M.D., Ph.D.*
Departments of *Radiation Oncology,yGastroenterology, andzGeneral Surgery, Saint-Louis Hospital, Paris, France;
Departments ofxMedical Oncology andkDigestive Surgery, Croix Saint-Simon Hospital, Paris, France;{Department of Colorectal Surgery, Beaujon Hospital, Clichy, France;#Department of Digestive Surgery, Lariboisie`re Hospital, Paris, France; and **Department of Gastroenterology, Avicenne Hospital, Bobigny, France
Received Mar 30, 2011, and in revised form May 30, 2011. Accepted for publication Jul 20, 2011
Summary
This retrospective analysis studied the use of gastrec- tomy, adjuvant 5FU and cisplatin chemotherapy followed by conformal radiotherapy and concurrent high-dose leucovorin and 5-fluorouracil (LV5FU2) in high-risk gastric cancer.
Treatment appeared feasible and overall and disease-free survival rates were compa- rable to those in the literature, with good local and regional disease control. Despite the intensification of post- operative chemotherapy, distant and peritoneal
Purpose:To analyze the efficacy, toxicity, and pattern of relapse after adjuvant cisplatin-based chemotherapy followed by three-dimensional irradiation and concomitant LV5FU2 chemo- therapy (high-dose leucovorin and 5-fluorouracil bolus plus continuous infusion) in the treat- ment of completely resected high-risk gastric cancer.
Methods and Materials:This was a retrospective analysis of 52 patients with high-risk gastric cancer initially treated by total/partial gastrectomy and lymphadenectomy between January 2002 and June 2007. Median age was 54 years (range, 36e75 years). Postoperative treatment con- sisted of 5-fluorouracil and cisplatin chemotherapy. Adjuvant chemotherapy was followed by three-dimensional conformal radiotherapy in the tumor bed and regional lymph nodes at 4500 cGy/25 fractions in association with concomitant chemotherapy. Concomitant chemotherapy con- sisted of a 2-h infusion of leucovorin (200 mg/m2) followed by a bolus of 5-fluorouracil (400 mg/
m2) and then a 44-h continuous infusion of 5-fluorouracil (2400e3600 mg/m2) given every 14 days, for three cycles (LV5FU2 protocol).
Results:Five-year overall and disease-free survival were 50% and 48%, respectively. Distant metastases and peritoneal spread were the most frequent sites of relapse (37% each). After multivar- iate analysis, only pathologic nodal status was significantly associated with disease-free and overall survival. Acute toxicities were essentially gastrointestinal and hematologic. One myocardial infarc- tion and one pulmonary embolism were also reported. Eighteen patients had a radiotherapy program interruption because of acute toxicity. All patients but 2 have completed radiotherapy.
Conclusion:Postoperative cisplatin-based chemotherapy followed by conformal radiotherapy in association with concurrent 5-fluorouracil seemed to be feasible and resulted in successful locore- gional control.Ó2012 Elsevier Inc.
Reprint requests to: Laurent Quero, M.D., M.Sc., Department of Radiation Oncology, Saint Louis Hospital, 1 Avenue Claude Vellefaux,
75010 Paris, France. Tel: (þ33) 1-42-49-90-34; Fax: (þ33) 1-42-49-44- 67; E-mail:laurent.quero@sls.aphp.fr
Conflict of interest: none.
Int J Radiation Oncol Biol Phys, Vol. 83, No. 2, pp. 574e580, 2012 0360-3016/$ - see front matterÓ2012 Elsevier Inc. All rights reserved.
doi:10.1016/j.ijrobp.2011.07.031
biology physics www.redjournal.org
recurrences remained the most frequent pattern of relapse.
Keywords:Gastric cancer, Postoperative, Cisplatin, Chemoradiotherapy, Conformal
Introduction
In 2002 gastric cancer was the fourth most common cancer world- wide, with an estimated 934,000 new cases per year, and the second most common cause of death from cancer, with 700,000 deaths per year(1). In the European Union, estimated new cases and deaths from gastric cancer in 2006 were 80,100 and 57,500, respectively(2).
In western countries gastric cancer has a poor prognosis, with a 5-year survival rate after surgery of approximately 20e30%(3e5).
The prognosis of patients with locoregionally confined disease depends on the extent of the primary tumor and the extent of lymph node (LN) involvement. Even after complete surgical resection with negative margins (R0 resection) plus D1 or D2 lymphadenectomy, many patients, particularly those with Stage III and IV (M0) disease, will eventually relapse. The patterns of disease recurrence have not only revealed a high rate of distant failure but also a high rate of locoregional relapses even after R0 resection (4, 6). Long-term survival is only achieved in 8e40% of patients with locoregionally advanced disease, which makes the evaluation of adjuvant or neo- adjuvant treatment options a priority for these patients.
The Southwest Oncology Group/Intergroup 0116 study was the first large randomized trial demonstrating a significant progression- free and overall survival benefit of 17% and 9% at 3 years’ follow-up, respectively, for patients receiving adjuvant combined chemo- radiotherapy(7). The chemotherapy regimen in this protocol con- sisted of three cycles of 5-fluorouracil (5-FU) bolus and folinic acid given according to the Mayo Clinic protocol. It is of interest to note that the comparison of the patterns of disease relapse in the treatment and observation groups in this study suggested that the adjuvant treatment was more effective in reducing the rate of local recurrence rather than the rate of distant metastasis. This indicates that bolus 5-FU/folinic acid did not significantly decrease the development of distant metastases.
We chose to propose to our locally advanced patients an active regimen before chemoradiotherapy to prevent metastatic evolution.
Recently a meta-analysis showed a statistically significant survival benefit with the addition of adjuvant chemotherapy in patients with resectable gastric cancer, but the optimal regimen is not defined(8).
Cisplatin chemotherapy has been demonstrated to be a more active drug in advanced/metastatic gastric carcinoma than 5-FU/folinic acid alone, which makes it an attractive option for the use in the adjuvant setting(9, 10).
In patients with advanced colorectal cancer, a bimonthly schedule of high-dose leucovorin (LV) and 5-FU bolus plus continuous infu- sion (LV5FU2) was more effective and less toxic than a monthly schedule of low-dose LVand 5-FU bolus (Mayo Clinic protocol)(11).
The endpoints of this study were to evaluate the efficacy, sites of relapse, and toxicity after postoperative chemotherapy followed by concomitant chemoradiotherapy.
Methods and Materials
Patient identification and selection
In this study we identified 52 patients with high-risk gastric adenocarcinoma who received postoperative chemotherapy and
radiotherapy combination according to our institutional protocol.
All patients had neither gross peritoneal seeding evidence during surgical exploration nor metastatic disease on preoperative thor- acoabdominal and pelvic CT.
Surgery
Surgery consisted of total or partial gastrectomy and D1 or D2 LN dissection. Spleen resection was performed at the surgeons’
discretion.
The percentage of patients who had D1 and D2 LN dissection was 71% (37 patients) and 15% (8 patients), respectively. Seven patients (14%) had limited lymphadenectomy (<10 LN).
Patients with gastric adenocarcinoma were referred for adju- vant treatment by surgeons after total or partial gastrectomy in case of serosa and/or LN involvement.
The radiation oncologist saw patients 1 month after surgery: if the performance status was 0 or 1 with an oral absorption World Health Organization (WHO) / Eastern Cooperative Oncology Group (ECOG) performance status was 0 or 1 with an oral absorption of 1000e1500 Kcal, patients were considered candidates for adjuvant treatment.
Adjuvant treatment
Institutional recommendations were to deliver three cycles of chemotherapy with 5-FUecisplatin followed by concomitant chemoradiotherapy.
The postoperative chemotherapy regimen consisted of a pro- tracted continuous infusion of 5-FU (1000 mg/m2i.v.) on Days 1e3, and short perfusion of cisplatin (50 mg/m2i.v.) on Days 1 and 2, every 21 days for three courses.
Postoperative chemotherapy was followed, 1 month latter, by conformal radiotherapy in association with concomitant chemo therapy.
Radiotherapy
Patients underwent a contrast-enhanced multislice helical plan- ning CT scan (Philips Medical Systems, Best, The Netherlands) with 5-mm slice thickness. Immobilization devices consisted of knee support and ankle stock. Images from CT were transferred to the PLATO treatment planning system (Veenendaal, The Netherlands) for contouring and performing the dosimetry.
We followed the recommendations of the Intergroup trial to define our target volumes(12). Patients were treated in the supine position with 10e18-MV photons. Radiotherapy delivered 4500 cGy to the planning target volume in 25 fractions of 180 cGy with a three- or four-field technique. The clinical target volume (CTV) included the gastric bed, anastomosis with a 2-cm proximal/distal margins, and regional LN areas.
The CTVs were delineated according to preoperative endo- scopic and imaging evaluations and preoperative and pathologic descriptions. Regional LN Levels 1 to12, according to the Japa- nese classification(13), were included into the CTV. For patients with cardia tumor, inferior paraesophageal LNs were also included
into the CTV, but LN Levels 13 and 14 were excluded. For patients with antral tumor, LN Levels 10 (splenic) and 14 (supe- rior mesenteric) were excluded.
The planning target volume consisted of the CTV plus a 0.5-cm margin in all directions.
Concomitant chemotherapy
Concomitant chemotherapy was a modified LV5FU2 chemotherapy regimen consisting of a 2-h infusion of LV (200 mg/m2) followed by a bolus of 5-FU (400 mg/m2) and then a 44-h continuous infusion of 5-FU (2400e3600 mg/m2) given every 14 days, for three cycles.
Follow-up, definition of relapse, and toxicities
Patients were followed-up at 4-month intervals for the first year, at 6-month intervals for the next 2 years, and annually thereafter. The follow-up evaluation consisted of physical examination, a complete blood count, and liver function test. All patients had thor- acoabdominalepelvic CTat 6-month intervals for the first 2 years and annually thereafter. Gastroscopy was performed in case of clinical symptoms. During the follow-up period, the first relapse site was used to determine local relapse, regional relapse, or distant metastasis.
Locoregional relapse was defined as recurrence at the anastomosis site, duodenal stump, tumor bed, or remnant stomach, or the regional LNs. We distinguished peritoneal relapses and distant metastasis (liver metastasis or metastasis of other extra-abdominal sites). Date of relapse was calculated from the date of surgery.
Toxicities were reported according to the National Cancer Institute Common Toxicity Criteria (NCI CTC), version 3.0.
A 25% chemotherapy dose reduction was recommended in case of Grade 3 toxicity during adjuvant chemotherapy. During concomitant chemoradiotherapy, a treatment break was also rec- ommended in case of Grade3 toxicity (especially gastrointestinal toxicity).
Parenteral nutrition support was administered in case of major malnutrition (body weight loss >10%). Administration of a 5-Hydroxytryptamine3 receptor antagonist and proton pump inhibitor was recommended during radiotherapy.
Statistical analysis
Survival was calculated with the Kaplan-Meier method(14), and differences were expressed at the 5% significance level, using a two-tailed logerank test(15).
Multivariate analysis of the data was performed using the Cox proportional hazards model (16). All calculations and survival display were done using STATA 9.0 statistical software (Stata- Corp, College Station, TX).
Results
Patient characteristics
From January 2002 to June 2007, 52 patients were consecutively treated at our institution (Table 1). The median age at the time of diagnosis was 53.5 years (range, 36e75 years); 21% were aged 65 years or older. The male/female ratio was 4:1. Nineteen patients
(37%) underwent subtotal gastrectomy and 33 (63%) total gastrec- tomy. The average number of resected LNs was 20 (range, 4e55).
Twenty-nine patients (56%) and 7 (14%) had involvement of the serosa and extension to adjacent organs or structures, respectively.
Only 1 patient had tumor at the resection margins on microscopic examination (R1).
Ninety-four percent of patients had LN involvement, with 4.5 median positive pathologic LNs (range, 0e22). Median ratio of nodal involvement was 25% (range, 0e100). Seventeen patients (33%) had major nodal involvement with more than 50%.
Table 1 Patient characteristics
Characteristic Patients (nZ52) Age (y)
Median (range) 54 (36e75)
<65 41
65 11 Sex
Male 41
Female 11
Type of gastrectomy
Total 33
Subtotal 19
Location of tumor
Distal third 26
Middle third 18
Proximal third 7
Remnant stomach 1
Extent of lymph node (LN) dissection
Median (range) 20 (4e55)
No. of dissected LNs<10 7
No. of dissected LNs 10e20 21
No. of dissected LNs>20 24
Pathologic tumor status (pT)
pT1/pT2 16
pT3 29
pT4 7
Pathologic nodal status (pN)
Median (range) 4.5 (0e22)
pN0 3
pN1 (1e6 positive nodes) 32
pN2 (7e15 positive nodes) 11
pN3 (>15 positive nodes) 6
Ratio of nodal involvement (pN%)
Median (range) 25 (0e100)
10% 11
10%e50% 24
>50% 17
Grade
Well to moderately differentiated 10
Poorly to undifferentiated 28
Unknown 14
AJCC stage
IeII 16
IIIA 18
IIIB 8
IV (M0) 10
Abbreviation:AJCCZAmerican Joint Committee on Cancer.
Values are number unless otherwise noted.
The stage distribution according to the American Joint Committee on CancereInternational Union Against Cancer clas- sification(17)was as follows: Stages IeII, 16 patients (31%); Stage IIIA, 18 patients (35%); Stage IIIB, 8 patients (15%); and Stage IV, 10 patients (19%).
Tumor location was in the proximal third of the stomach for 7 patients (14%), in the middle third for 18 patients (35%), and in the distal third for 26 patients (50%).
Feasibility
Adjuvant chemotherapy
Because of cisplatin contraindication, 2 patients received a combination of oxaliplatin and 5-FU and 1 patient a combination of irinotecan and 5-FU (regimen consisted of a 2-h infusion of oxaliplatin [85 mg/m2] or irinotecan [180 mg/m2] on day 1, a 2-h infusion of leucovorin [200 mg/m2] followed by a bolus of 5-FU [400 mg/m2], and then a 44-h continuous infusion of 5-FU [2400 mg/m2] delivered every 14 days for six courses). Three patients did not receive postoperative chemotherapy. Forty-six patients received the planned protocol.
Radiotherapy
The median total tumor dose delivered was 45 Gy (range, 14e46 Gy), and median duration of radiotherapy treatment was 38 days (range, 9e57 days). Treatment interruption was observed in 18 patients. Two patients did not complete radiotherapy treatment because of febrileCandidaesophagitis and severe gastrointestinal toxicity.
Median size of the CTV was 254 cm3(range, 92e770 cm3), and median size of the planning target volume was 475 cm3(range, 229e1138 cm3).
Concomitant chemotherapy during radiotherapy Forty-four patients received the planned protocol. Three patients received oral capecitabine (825 mg/m2 b.i.d.) on each day of radiotherapy. Five patients did not receive any chemotherapy during radiotherapy for toxicity reasons.
Overall and disease-free survival
The median follow-up was 33.9 months for all patients and 40.8 months for patients who were alive at the last follow-up. Overall survival was 63% at 3 years and 50% at 5 years (Fig. 1).
Disease-free survival was 52% at 3 years and 48% at 5 years (Fig. 2).
After multivariate analysis, only pathologic nodal status (pN) was predictive of disease-free survival (Fig. 3); patients with six or fewer positive LNs (pN0e1) had a probability of 57% to be alive without disease at 5 years vs. 32% and 18% for patients with 7e15 and>15 positive LNs, respectively (pZ0.02).
Patterns of relapse
Twenty-seven patients (52%) have relapsed after treatment (Fig. 4). Overall, distant, and peritoneal relapses were the most common sites of relapse (37% each), followed by locoregional relapse (26%). Peritoneum was the most common site of relapse (5 patients) for patients with a single pattern of relapse; bone and LNs were the second and third most frequent sites.
In-field recurrence after radiotherapy was observed in 10 patients (19%): 4 patients had anastomotic recurrence, 3 had regional LNs recurrence, and 3 had gastric bed recurrence. We did not observed local or LN recurrences outside CTV.
No significant difference was seen between proximal and distal tumor location in terms of locoregional control (pZ0.45) (data not shown).
Treatment tolerance
During postoperative chemotherapy, the most common toxicities were hematologic and gastrointestinal (Table 2). Neither severe neuropathy nor renal toxicities were observed. Severe thrombo- cytopenia (Grade 3) according to NCI CTC v3.0 was observed in 1 patient (2%), and Grade 3 neutropenia was observed in 3 patients (6%). Neither febrile neutropenia nor Grade 4 hematologic toxicities were observed.
Grade 3 vomiting was observed in 4 patients (8%), and Grade 3 diarrhea was observed in 2 patients (4%). Grade 3 subocclusion was observed in 1 patient (2%). Neither Grade 4 gastrointestinal nor hand-foot syndrome toxicities were observed.
During concomitant chemoradiotherapy, Grade 3 vomiting and Grade 3 esophagitis were observed in 3 (6%) and 6 (12%) patients, respectively. Thirteen patients (25%) received nutrition support during postoperative treatment (11 parenteral and 2 enteral).
Grade 3 diarrhea was observed in 1 patient. No gastrointestinal Grade 4 toxicity was observed.
Fig. 1. Overall survival.
Fig. 2. Disease-free survival.
Nonfebrile Grade 4 neutropenia was observed in 2 patients (4%).
Myocardial infarction during 5-FU infusion was reported in 1 patient. Pulmonary embolism was reported in 1 patient.
Discussion
Gastric cancer has a poor prognosis because it is usually diagnosed in an advanced stage, with serosa extension and/or LN invasion.
For the last decade, several postoperative treatment strategies have been explored in randomized trials, such as postoperative chemoradiotherapy, perioperative chemotherapy, or adjuvant chemotherapy.
The U.S. Intergroup Southwest Oncology Group 9008/Inter- group 0116 Phase III trial has shown, after a median follow-up of
>6 years, that postoperative chemoradiotherapy significantly improved median duration of overall survival compared with
surgery alone (35 vs. 26 months, respectively,pZ0.006)(7, 18).
Improvement in survival and disease-free survival by post- operative chemoradiotherapy was also confirmed after 10 years’
median follow-up, with hazard ratio 1.32 and 1.51, respectively, favoring the chemoradiotherapy group (19). In this study, criti- cisms were made about the extent of LN resection (54%, 36%, and 10% of patients underwent D0, D1, and D2 resection, respec- tively) and the high incidence of acute toxicities (41% Grade 3 and 4% Grade 4), essentially hematologic and gastrointestinal toxic effects. Seventeen percent of patients did not complete treatment because of toxic effects, 8% refused treatment, and 5%
had progression of disease while receiving treatment. Acute toxicities could be explained by use of old radiotherapy tech- niques and an old chemotherapy regimen (5-FU bolus).
The major limitation of our study is related to its retrospective and nonrandomized nature. With 50% 5-year overall survival, our results are comparable to other previous postoperative chemoradiotherapy studies. Most of the relapses were distant or peritoneal, despite a 5-FUecisplatineadjuvant chemotherapy regimen. New chemo- therapy schedules must be evaluated. We did not observe any local relapse outside our CTV. Thus the recommendations of the U.S.
Intergroup(12)regarding the volume of radiotherapy must be fol- lowed, even with the use of modern techniques. However, the rate of local relapse is significant (26%): the possibility of boost dose in high- risk regions must perhaps be discussed in some cases by using three- dimensional (3D) radiotherapy or intensity-modulated radiotherapy, as supported by some clinical experiences. A higher dose to the CTV while minimizing the doses to the organs at risk would rationally improve locoregional control and decrease in-field relapses.
With the use of a 3D conformal technique, the complete radiotherapy schedule could be performed in 96% of our patients.
A concomitant 5-FU regimen could be given to 85% of the patients, but 34% of patients had an interruption of the radio- therapy course. The treatment was moderately tolerated, with mainly manageable gastrointestinal secondary effects. Twenty-five percent of the patients received nutrition support during the treatment. Some slight changes in the chemotherapy schedule or doses could reduce toxicity and perhaps allow the safe adminis- tration of higher radiotherapy doses to the CTV.
Baeza et al. (20) reported 54% 5-year overall survival after adjuvant chemoradiotherapy, whole-abdomen irradiation, and concomitant 5-FU in completely resected, high-risk gastric cancer.
Arcangeli et al. (21) reported 40% 5-year overall survival after postoperative concomitant hyperfractionated radiotherapy and 5-FU protracted venous infusion. Recently, Leonget al.(22)reported in a multicentric prospective study 62% 3-year overall survival after one Fig. 3. Disease-free survival curves according to pathologic
nodal status. Blue line represents patients with six or fewer positive lymph nodes (pN0e1). Red line represents patients with 7 to 15 positive lymph nodes. Green line represents patients with more than 15 positive lymph nodes. Differences between curves are statistically significant (pZ0.02).
Fig. 4. Pattern of failure.
Table 2 Cumulative incidence of Grade 3þ acute compli- cations according to NCI CTC v3.0
Complication Grade 3,n(%) Grade 4,n(%)
Nausea/vomiting 4þ3 (14) 0
Diarrhea 2þ1 (6) 0
Esophagitis 6 (12) 0
Subocclusion 1 (2) 0
Neutropenia 3 (6) 2(4)
Thrombocytopenia 1 (2) 0
Myocardial infarction 0 1 (2)
Pulmonary embolism 0 1 (2)
Abbreviation: NCI CTC Z National Cancer Institute Common Toxicity Criteria.
cycle of epirubicine, cisplatin, and 5-FU (ECF) followed by 3D conformal radiotherapy with concurrent infusional 5-FU and two additional cycles of ECF. Sixty-six percent of patients developed Grade 3/4 neutropenia. Grade 3/4 gastrointestinal toxicity occurred in 28% of patients(22). A meta-analysis of 708 patients with resectable gastric carcinoma initially treated by surgery showed that post- operative chemoradiotherapy reduced 5-year overall mortality by 55% compared with surgery alone (39% vs. 23%)(23). A Korean observational study has shown that surgery with extended D2 LN resection followed by postoperative chemoradiotherapy, delivered according to the U.S. Intergroup protocol, significantly improved 5-year overall survival compared with surgery alone (57% vs. 51%, pZ0.02)(24). Although a D2 LN dissection was performed, this study confirmed that chemoradiotherapy was an effective adjuvant treatment in high risk gastric cancer.
A British Medical Research Council randomized trial demonstrated that perioperative chemotherapy (three cycles of ECF regimen [epirubicin, cisplatin, and continuous 5-FU], given before and after surgery) significantly improved 5-year survival, from 23.0% with surgery alone to 36.3%(25). In this study, it is important to note that 34% of patients who completed preop- erative chemotherapy and surgery did not receive postoperative chemotherapy, because of early disease progression, patient refusal, or treatment toxicities. The French FNCLCC (Federa- tion Nationale des Centres de Lutte Contre le Cancer) ACCORD07-FFCD 9703 randomized trial reported, in patients with resectable adenocarcinoma of the stomach and lower esophagus, that preoperative 5-FU and cisplatin chemotherapy significantly improved 5-year overall and disease-free survival compared with surgery alone: 38% vs. 24% and 34% vs. 21%, respectively(26).
The Japanese Adjuvant Chemotherapy Trial of TS-1 for Gastric Cancer randomized trial has shown that adjuvant S-1 oral fluo- ropyrimidine chemotherapy, after gastrectomy with extended (D2) lymph-node dissection, for Stage II or III gastric cancer, improved 3-year overall survival compared with surgery alone: 80.1% vs.
70.1%. Adjuvant S-1 chemotherapy was well tolerated, with only 6% anorexia, 3.7% nausea, and 3.1% diarrhea (Grade 3 or 4 according to NCI CTC v2.0 criteria)(27). Recently a meta-analysis of 3781 patients treated for resectable gastric cancer showed that adjuvant chemotherapy increased 5-year overall and disease-free survival by 18% compared with surgery alone (p<0.001). The absolute benefit of adjuvant chemotherapy was only 5%, 5-year overall survival increased from 50% to 55%, and 5-year disease- free survival increased from 51% to 56%(8).
In view of these results, the place of adjuvant chemoradiotherapy is challenged by perioperative chemotherapy. Because the local relapse rate remains important, it seems logical to propose adjuvant chemoradiotherapy in case of persistent nodal or gastric disease after preoperative chemotherapy.
Currently Korean and Dutch/Swedish Phase III studies are ongoing to define the role of postoperative concurrent chemo- radiotherapy in comparison with chemotherapy alone in patients with gastric cancer treated by surgery with D2 lymphadenectomy.
The Korean trial (ClinicalTrials.gov ID NCT00323830) is comparing capecitabine/cisplatin chemotherapy vs. capecitabine/
cisplatin with radiotherapy (chemoradiotherapy); the primary endpoint is disease-free survival. The Dutch/Swedish trial (Randomized Phase III Trial of Adjuvant Chemotherapy or Che- moradiotherapy in Resectable Gastric Cancer (CRITICS) study;
ClinicalTrials.gov ID NCT00407186) is comparing three post- operative courses of epirubicin, cisplatin, and capecitabine
chemotherapy vs. chemoradiotherapy with capecitabine and cisplatin in patients with gastric cancer treated by three preoper- ative courses of epirubicin, cisplatin, and capecitabine chemo- therapy followed by surgery with D2 lymphadenectomy without splenectomy and pan createctomy.
Conclusion
Postoperative cisplatin-based chemotherapy followed by conformal radiotherapy in association with concurrent 5-FU seemed to be feasible. Overall and disease-free survival rates are comparable to those previously reported in the literature, with good local and regional disease control. Despite the intensification of postoperative chemotherapy with cisplatin, distant and peritoneal recurrences remain the most frequent pattern of relapse.
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