ORIGINAL RESEARCH

Management Strategies for Locoregional Recurrencein Early-Stage Gastric Cancer: Retrospective Analysisand Comprehensive Literature Review

Ahmed Salem & Sameh Hashem & Layth Y. I. Mula-Hussain & Issa Mohammed &

Ala’a Nour & Wael Shelpai & Faiez Daoud & Basem Morcos & Yasser Yamin &

Imad Jaradat & Jamal Khader & Abdelatief Almousa

# Springer Science+Business Media, LLC 2010

AbstractObjective To present a comprehensive account and literaturereview addressing the anatomical distribution, natural history,and management strategies for locoregional recurrence inearly-stage gastric cancer (EGC).Patients and methods Retrospective chart review of patientspresenting with EGC recurrence at King Hussein CancerCenter (Amman, Jordan) between July 2006 and May 2009.A literature review of publications addressing recurrencefollowing surgery for EGC was undertaken via a systematicsearch of PUBMED database and National ComprehensiveCancer Network (NCCN) guideline updates.Results Seventeen patients presented with EGC, three ofwhom (17.6%) were pathologically staged as T2N1 [1/33lymph nodes (LNs)], T1N0, and T1N0 were afflicted byrecurrence following R0 partial gastrectomy. Literature

review yielded 18 studies specifically addressing recurrencein EGC. Several management strategies have been proposedfor isolated recurrence following gastrectomy in EGC. NCCNclinical practice guideline updates do not take into consider-ation whether the recurrence is isolated or widespread andwhether the initial stage is early or advanced.Conclusions While acknowledging the limitations of thisstudy, including the small sample size and the short follow-upperiod, it appears clear that oncologic treatment is possible forEGC recurrence, particularly, in patients with isolated relapse.Guideline updates should differentiate between managementstrategies suitable for recurrence occurring in early versusadvanced initial cancer stage.

Keywords Gastric cancer . Recurrence . Radiotherapy .

Surgery . Chemotherapy

Introduction

Gastric adenocarcinoma is currently the fourth mostcommon cancer worldwide with approximately 930,000new cases and 700,000 deaths per year [1, 2]. Despite thedeclining incidence in the west, stomach cancer is stillconsidered a significant health challenge because diagnosisis often made at an advanced stage with nodal involvementand/or extension to adjacent organs [3]. Early-stage diseaseconfers excellent long-term outcome if properly treated [4],with surgery being the sole curative modality [5]. Localrecurrence is estimated to occur in 30–80% of patients withadvanced stage cancer [3]. The incidence, natural history,anatomical distribution and therapeutic modalities forrecurrence following curative surgery in early-stage gastric

A. Salem : S. Hashem : L. Y. I. Mula-Hussain : I. Mohammed :A. Nour : I. Jaradat : J. Khader :A. Almousa (*)Department of Radiation Oncology, King Hussein Cancer Center,Amman, Jordane-mail: aalmousa@khcc.jo

W. ShelpaiClinical Research and Cancer Registry,King Hussein Cancer Center,Amman, Jordan

F. Daoud : B. MorcosDepartment of Surgical Oncology, King Hussein Cancer Center,Amman, Jordan

Y. YaminDepartment of Medical Oncology, King Hussein Cancer Center,Amman, Jordan

J Gastrointest CancDOI 10.1007/s12029-010-9207-3

cancer (EGC), however, remain unknown. We present adetailed and comprehensive account of the therapeuticregimens and disease outcome of this poorly reported entity.

Patients and methods

Between July 2006 and May 2009, 237 patients with gastriccarcinoma were treated at King Hussein Cancer Center(Amman, Jordan). Records of patients with early gastricadenocarcinoma (T1 and 2, N1) were retrospectivelyreviewed following acquisition of Institutional ReviewBoard approval with special reference to the incidence,location and management of cancer recurrence. Tumorslocated at the gastroesophageal junction were excludedfrom this study. A review of literature addressing recurrencefollowing surgery for EGC was undertaken via a systematicsearch of PUBMED database for English-language articlesand abstracts published from July 1987 and NationalComprehensive Cancer Network (NCCN) guidelineupdates. Three abstracts in Japanese and one abstract inKorean addressing the role of surgery and chemotherapy inrecurrent gastric cancer were included in this review.

Results

Seventeen patients presented with EGC (7.2%); three ofwhom (17.6%) pathologically staged as T2N1 [1/33 lymphnodes (LNs)], T1N0 and T1N0 were afflicted by recurrencefollowing R0 partial gastrectomy (Table 1). The first patientreceived adjuvant chemoradiation according to MacDonald’sprotocol [6]. Time to recurrence was 30, 33, and 9 months,respectively. Recurrence was in the regional LNs (mesentericand para-aortic) in first two patients and in the anastomoticsurgical bed in the third. Patients with nodal recurrenceopted not to take the proposed chemotherapeutic regimensconsequent to informed decision and remain alive withdisease 18 and 12 months into follow-up, respectively. Thepatient with anastomotic recurrence underwent completiongastrectomy and remained alive and free from disease28 months into follow-up. Literature review yielded 18studies specifically addressing recurrence in EGC.

Definition of early gastric cancer and the incidenceof recurrence

“Early gastric cancer” is a term used infrequently to definetumors which are potentially “curable” by means of surgicalresection only [7]. Generally, this term encompasses T1tumors which are located within the mucosa (T1a) or reachthe submucosa (T1b) [8]; however, any potentially curable T

able

1Patient

characters

andou

tcom

e

Num

ber

Sex

Age

1ºtumor

stage

Treatmentof

1ºtumor

Locationof

recurrence

Tim

eto

recurrence

(mon

ths)

Patho

logical

confirmation

ofrecurrence

Possiblecause

Presenting

symptom

Treatmentof

recurrence

Follow-up

from

recurrence

(months)

Outcome

1M

35pT

1N0M

0PartialGastrectomy

Anastom

otic

site

9Yes

LVIPositive

tumor

marginno

tdetected

bypatholog

ist

Epigastricpain

Com

pletion

Gasterctomy

28Aliv

eNED

2F

50pT

1N0M

0DistalGastrectomy

RegionalLNs

(Para-aortic

LNs)

33Yes

Poorlydifferentiated

histology

Epigastricpain

None(refused

treatm

ent)

12Aliv

ewith

disease

3f

42pT

2N1M

0PartialGastrectomy

andadjuvant

CRT

(MacDon

aldprotocol)

RegionalLNs

(Mesentric

LNs)

30No

Poorlydifferentiated

histology,

LVI

Asymptom

atic

Observatio

n18

Aliv

ewith

disease

J Gastrointest Canc

gastric tumor could be included in this definition. Nodalmetastasis (N1, 2)—once synonymous with advancedgastric cancer—does not always preclude curative resection.

The incidence of EGC has climbed in recent decadesconsequent to developments in diagnostic approaches [7].In Japan, screening programs have enabled detection ofgastric cancer at very early stages [9]. In comparison, EGCstill constitutes less than 10% of gastric cancer cases in theWest [8]. Surgical resection is the mainstay of treatment forgastric adenocarcinoma [10]. Less aggressive therapeuticalternatives for EGC, in addition, include endoscopicmucosal resection, wedge resection, and laparoscopic-assistedgastrectomy [11].

The rate of recurrence in EGC treated by D2 gastrectomy isreported to vary between 1.3% to 12.2% [7, 12–17] (Table 2).Median time to recurrence is 16 months, and 82% of patientsrecur in the first 2 years after surgical treatment [18].Potential sites for recurrence include the surgical bed,remnant stomach, anastomotic staple line, duodenal stump,and regional LNs [3]. The incidence of lymphogenousrecurrence is related to the extent of LN dissectionperformed [19]. Hematogenous spread, however, is probablythe most common pattern of recurrence [12].

In general, gastric cancer recurrence was thought torepresent advanced cancer progression [19]. In reality,successful oncologic treatment is often possible, particularly,in patients with isolated relapse of early-stage disease. Thereare, however, limited reports addressing the outcome, thera-peutic regimen, and prognostic factors in such patients [20].

Standard management of early-stage gastricand esophagogastric junction tumors

Standard treatment for EGC is complete surgical resection(subtotal or total gastrectomy), D1 or D2 LN dissection,followed by reconstruction with gastrojejunostomy. In thesame manner, surgical resection is the mainstay treatment forearly esophagogastric junction tumors; however, the required

extent of surgical resection is dependent on the anatomiclocation of the primary tumor. According to the AEGclassification; adenocarcinomas of the distal esophagus(AEG type I) are distinguished from tumors of the anatomicalcardia (AEG type II) and subcardiac region (AEG type III).Total gastrectomy with resection of the distal esophagus is asuitable approach for AEG type II and III tumors [21]. Siewertand colleagues [22] confirm such recommendations viareporting the surgical experience of 1,002 patients withadenocarcinoma of the esophagogastric junction. Esophagec-tomy does not appear to offer any survival benefit overextended gastrectomy in these patients and is associated withsignificantly higher morbidity [23]. In comparison, AEG typeI tumors require an esophagectomy for potential cure [21].

Diagnostic alternatives for detection of recurrence

Contrast-enhanced computed tomography (CT) remains thestandard radiological method for detection of gastric cancerrecurrence irrespective of initial tumor stage. Park et al.[24] suggested a potential role of positron emission tomog-raphy (PET)/CT in detection of gastric cancer recurrence;however, more comprehensive reports narrate that theaddition of PET/CT does not appear to increase the diagnosticaccuracy of contrast-enhanced CT in the detection of recurredgastric malignancy [1]. Definitive diagnosis requires patho-logical confirmation through CT- or ultrasound-guided needlebiopsy and/or reoperation. Even though such approachesoften prove to be technically demanding consequent to lesionsize, depth, and proximity to great vessels and/or organs, theyremain mandatory prior to the delivery of radical therapy.

Isolated versus widespread recurrence in advancedversus early gastric cancer

It is estimated that 5% of patients with EGC die fromrecurrent disease [25]. Survival in our patients contrasts

Table 2 The incidence and location of recurrence in six large EGC series

Study Year Numberof patients

Clinical stage Pattern of failure after gastrectomy

Total failure Nodal Nodal andperitoneal

PeritonealOnly

Anastomotic/gastric stump

Distant

Sano et al. [14] 1993 1,486 EGC(Stages I–IIc)

20 (1.3%) 4 (20%) 2 (10%) 1 (5%) Not mentioned 13 (65%)

Kim et al. [7] 2009 1,786 EGC 32 (1.79%) 9 (28.1%) 10 (31.3%) 1 (3.1%) Not mentioned 12 (37.5%)

Folli et al. [13] 1995 223 EGC 22 (9.9%) 8 (36.4%) Not mentioned 14 (63.6%)

Wu et al. [15] 2008 245 EGC 30 (12.24%) – 4 (13.3%) 2 (6.7%) 16 (53.3%) 8 (26.7%)

Habu et al. [16] 1987 304 EGC 6 (1.97%) 2 (33.3%) 4 (66.7%)

Ichiyoshi et al. [17] 1990 503 EGC 17 (3.4%) 3 (17.6%) – – 5 (29.4%) 9 (53%)

J Gastrointest Canc

median survival following recurrence in advanced gastriccancer which is estimated at 5 months [12, 26]. Similarly,prior reports have narrated that patients with isolatedrecurrence have a survival rate that is superior to thosewho presented with multiple or widespread dissemination[20]. More specifically, Park et al. [27] demonstratedsuperior survival in patients with isolated para-aorticLN (PALN) metastasis than those whose recurrence waslocated elsewhere. Such observations provide conclusiveaffirmation that isolated recurrence in EGC more closelyrepresents indolent disease rather than advanced cancerprogression.

Prevention of recurrence

Subsequent to inherent difficulties in successfully treatinggastric recurrence, emphasis has currently been focused onpresenting therapeutic alternatives that can potentiallyprevent recurrence of gastric malignancy. Extensive D2lymphadenectomy improves staging accuracy and mightreduce locoregional relapse, particularly, in the lymphaticbasins [2]. This is especially true for patients with pT1–2tumors; a statistically significant negative correlationbetween the number of dissected LNs and recurrence rateis consistently being reported [25]. Preoperative chemo-radiation can decrease the risk of peritoneal seedling atsurgery [26]; however, utilization of neo-adjuvant chemo-radiation in EGC has not been previously reported. Thebenefit of adjuvant chemoradiation on locoregional controlin advanced gastric cancer is undeniable [2]; nonetheless,postoperative chemoradiation is probably not warranted inpatients with EGC owing to the toxicity associated with theformer regimen. Risk factors for recurrence include olderage, submucosal tumors, lymphatic invasion, and c-erB-2immunopositivity [7, 12]. Presence of these risks mightwarrant closer follow-up and consideration for furthertreatment.

Histological variables relating to recurrence

Histological subtypes of gastric cancer exhibit differentbiological behavior that may reflect altered recurrence

patterns [5, 28, 29]. On one hand, intestinal-type adeno-carcinomas are more prone to hepatic metastases, whilediffuse-type adenocarcinomas more frequently result inperitoneal dissemination [2]. Micrometastasis is a possibleexplanation for recurrence in node-negative EGC [12].Multiple lymphatic pathways make it difficult to performcomplete nodal dissection during gastrectomy providing apotential haven for recurrence in the regional LNs andmetastasis elsewhere [30]. On the other hand, vascularinvasion of submucosal cancer cells might be implicated asa possible mechanism for distant recurrence [12].

Management alternatives

Palliative care has traditionally been offered to patients withnodal metastasis following gastrectomy; however, there isgrowing consensus to consider isolated gastric cancerrecurrence, particularly, in early-stage disease—in similarityto colorectal cancer—potentially salvageable via varioustherapies [19]. NCCN version 1.2010 clinical practiceguidelines [31] dictate that recurrence following gastriccancer is to be treated according to Karnofsky performancestatus (KPS). Patients with KPS>60% are to be treated bychemotherapy, clinical trials, or best supportive care, whilepatients with KPS≤60% are to be offered best supportivecare. Unfortunately, NCCN updates do not take intoconsideration whether the recurrence is isolated or wide-spread, and whether the initial stage is early or advanced.

Surgical Management

Repeat surgery for recurrent gastric cancer can serve as asalvage modality for local control or as a palliativealternative for intestinal obstruction, obstructive jaundiceand/or uretric obstruction [19]. In such cases, operativemanagement can be technically difficult and is thought tobe associated with high mortality. Park et al. [32] reportedan operative mortality of 10.5%. Furthermore, completeresection is possible in only 17% of patients [32]. However,and since complete surgical excision has been associatedwith significant survival benefit, aggressive surgicalapproaches are strongly recommended [33]. Operative

Table 3 Surgical management for EGC recurrence

Study Year Numberof patients

Medianage

Primary tumorstage

Location ofrecurrence

Time torecurrence

Treatment Symptomaticrelief

MedianSurvival

de Liaño et al. [38] 2008 3 80 T1a-2a, N0-1(3/39LNs)

Anastomotic line Not clear Surgical excision 3/3 (100%) 30 months

Carboni et al. [39] 2005 1 58 T2N1 Gastric bed 50 months Surgicalexcision + CTX

Not clear 11 months

J Gastrointest Canc

management for isolated nodal recurrence is more appealing.Nashimoto et al. [34] reported a case in which surgicaldissection of an isolated PALN metastasis resulted in a6-year survival (Table 3).

Role of chemotherapy

Studies have demonstrated mixed response following admin-istration of chemotherapy for recurrent gastric cancer [29, 35].Teraishi et al. [36] reported a case of recurrent gastric cancerto the PALNs with marked response to chemotherapyconsisting of S-1 with more than 21 months of progression-free survival. Murakami et al. [37] narrated the successful useof TS-1 in conjunction with 5-fluorouracil, mitomycin C, andcisplatin in patients with liver, PALN, and peritonealrecurrence following gastrectomy for gastric cancer.

Role of radiotherapy

The role of conventional radiotherapy in recurrent gastriccancer is limited due to the proximity of the involved LNsto critical organs, such as the spinal cord, intestine, andcolon, that often prevent the delivery of sufficient radiationdose for adequate local control [19]. The inapplicability ofconventional irradiation gradually shifted the attentiontoward a more stereotactic approach in patients withisolated relapse. Kim et al. [19] reported promising resultswith stereotactic body radiotherapy using CyberKnife®(Accuray Inc., Sunnyvale, CA, USA) at doses between 45and 51 Gy over three fractions for patients with isolatedPALN recurrence (Table 4).

Future directions

Molecular genetic studies are improving our understanding ofthe biologic profile and clinical behavior of gastric cancer andpromise to enhance prognostic stratification of patients withthe aim of developing individualized new therapies [2]. Novelalternatives incorporating molecularly directed targeted ther-apies are set to play an increasing role in the management ofgastric cancer [2]. HER-2 is amplified in 18–27% of gastriccancer; however, the role of Trastuzumab, a recombinanthumanized anti-HER-2 monoclonal antibody, in recurrentgastric cancer needs further refinement [40].

Conclusions

The natural history and therapeutic outcome for recurrencefollowing EGC is in variance to recurrence following T

able

4IrradiationforEGC

Study

Year

Num

ber

ofpatients

Median

Age

Primary

tumor

stage

Locationof

recurrence

Tim

eof

recurrence

MedianRT

dose

Com

plete

respon

sePartial

respon

seSym

tomatic

relief

Tox

icity

Mediansurvival

Sun

etal.[30]

Inpress

3758

7TxN

O-2

RegionalLNs

12.2

mon

ths

50Gy/25

Fxa

11(29.7%

)20

(54.1%

)19

/21(90.5%

)Fivepatientshad

Grade

2toxicity

11.4

mon

ths

Kim

etal.[19]

2009

250

.5II

Isolated

PALN

28.5

mon

ths

46.5/3Fx(SBRT)b

2(100

%)

02/2(100

%)

Grade

1on

ly32

.5mon

ths

aPatientsdidnotreceivechem

oradiatio

nat

timeof

initial

disease

bGTV:PET/CTvisualizationof

tumor;PTV:GTV

plus

2–3mm

margin

Bothpatientsreceived

chem

otherapy

basedon

5-FU

before

SBRT

J Gastrointest Canc

advanced stage disease. Oncologic treatment is possible inEGC recurrence, particularly, in patients with isolatedrelapse. Guideline updates should differentiate betweenstrategies suitable for early rather than advanced initialcancer stage. The presence of the above-stated risk factorsmight warrant closer follow-up.

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