Original Communications

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ReprintGeneraland Den951-851

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� 2011

doi:10.1

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Operative treatment for metachronouspulmonary metastasis from esophagealcarcinomaHiroshi Ichikawa, MD,a Shin-ichi Kosugi, MD,a Satoru Nakagawa, MD,b Tatsuo Kanda, MD,a

Masanori Tsuchida, MD,c Teruaki Koike, MD,d Otsuo Tanaka, MD,b andKatsuyoshi Hatakeyama, MD,a

Niigata, Japan

Background. The clinical significance of operative treatment for metachronous pulmonary metastasisfrom esophageal carcinoma is unclear.Methods. We retrospectively reviewed 23 consecutive patients who underwent operative resection formetachronous pulmonary metastasis from esophageal carcinoma from 1991 to 2008. Patient baselinecharacteristics, survival probability, and prognostic factors were analyzed. The median follow-up periodwas 31 months for surviving patients.Results. There were 19men and 4women, with amedian age of 66 years at the time of pulmonary resection.Themedian disease-free interval was 15.5months. Cervical or mediastinal lymph nodemetastases precededpulmonary metastases in 4 patients. Seven patients (30.4%) had multiple metastases with a maximumnumber of 4. The median operative time and blood loss were 94.5 minutes and 18 mL, respectively. Themedian length of postoperative stay was 12.5 days. The predicted 1-, 3-, and 5-year survival rates using theKaplan-Meier method were 73.9%, 43.5%, and 43.5%, respectively, with a median survival time of28.7 months. Univariate analysis revealed that an extrapulmonary metastasis as the initial recurrence sitewas an unfavorable prognostic factor (P = .0411). Multivariate analyses, however, did not identify theinitial recurrence site as an independent prognostic factor (P = .0542).Conclusion. Operative resection for metachronous pulmonary metastasis from esophageal carcinoma isan acceptable treatment. This study of a limited number of patients may have created a constitutionalselection bias. An antecedent extrapulmonary metastasis was found to be an unfavorable prognosticfactor. (Surgery 2011;149:164-70.)

From the Division of Digestive and General Surgery,a Niigata University Graduate School of Medical andDental Sciences; the Department of Surgery,b Niigata Cancer Center Hospital; Division of Thoracic andCardiovascular Surgery,c Niigata University Graduate School of Medical and Dental Sciences; and theDepartment of Chest Surgery,d Niigata Cancer Center Hospital, Niigata, Japan

RECENT ADVANCES IN MULTIMODAL TREATMENT includingradical esophagectomy with extensive lymphade-nectomy, adjuvant therapy, and definitive chemora-diotherapy (CRT) improved the prognosis ofpatients with esophageal carcinoma.1-4 Recurrentdisease, however,may develop in 27--53%of patientsafter radical esophagectomy,2,5-11 with a median

d for publication July 22, 2010.

requests: Tatsuo Kanda, MD, Division of Digestive andSurgery, Niigata University Graduate School of Medicaltal Sciences, 1-757 Asahimachi-dori, Chuou-ku, Niigata0, Japan. E-mail: kandat@med.niigata-u.ac.jp.

60/$ - see front matter

Mosby, Inc. All rights reserved.

016/j.surg.2010.07.047

URGERY

survival time after the recurrence of 2.7 months to9.0 months.5-7,10-12 Patients with hematogenousrecurrence have a poorer prognosis than patientswith locoregional recurrence.10

Metachronous pulmonary metastasis from esoph-ageal carcinoma is seen in 17.5--41.4% of hematog-enous recurrence cases and is among the mainrecurrence patterns.8,10,11 Pulmonary metastasis isoften detected as multiple lesions or in combinationwith extrapulmonarymetastases. Therefore, systemicchemotherapy is usually selected for the treatment ofthis disease.With regard to colorectal carcinoma, op-erative intervention for metachronous pulmonarymetastasis has been reported by several authors andis widely accepted.13-20 However, the clinical signifi-cance of operative intervention for metachronous

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pulmonary metastasis from esophageal carcinoma isunclear, with only 1 retrospective study and a few casereports published to date.21,22

The aim of this study was to determine theclinicopathologic characteristics and the prognosisof patients who underwent operative interventionfor metachronous pulmonary metastasis fromesophageal carcinoma.

PATIENTS AND METHODS

We retrospectively reviewed 23 consecutivepatients who underwent operative resection formetachronous pulmonary metastasis from esopha-geal carcinoma in the Niigata University Medicaland Dental Hospital and the Niigata Cancer Cen-ter Hospital between 1991 and 2008. All but1 patient underwent initial treatment for primaryesophageal carcinoma at our institutions between1989 and 2007. A total of 1,191 patients underwentesophagectomy during this period. The primarytumor stages were classified according to thetumor node metastasis (TNM) classification systemof the International Union Against Cancer(UICC).23 Pathologic classification was used for20 patients who underwent esophagectomy; clini-cal classification was used for the remaining 3patients who received definitive CRT. Finally, 19patients underwent pulmonary metastasectomyout of the 1,191 who had undergone esophagec-tomy in our institutions (1.7%). The quality oftumor clearance was determined according to theUICC-R classification system.23 Patients underwentphysical and blood biochemistry examinationsevery 3 months after the initial treatment as a reg-ular checkup. Chest radiographs and computedtomography of the neck, chest, and abdomenwere performed at least once a year. The disease-free interval (DFI) was calculated from the dateof esophagectomy or the date confirming completecontrol of primary and/or metastatic diseases, untilthe date of pulmonary metastasis diagnosis. Carcino-embryonic antigen (CEA) and squamous cellcarcinoma antigen (SCC) levels were assessed be-fore thoracotomy, with the cutoff values of 5 and1.5 ng/mL, respectively.

Selection criteria for pulmonary metastasec-tomy were as follows: (1) The primary tumor wascontrolled by the initial treatment; (2) there wereno distant metastases except for pulmonarylesions---when there were extrapulmonary recur-rences, they had to be controlled by additionaltreatment; (3) regardless of the tumor numberand location, curative (R0) resection was expected;and (4) patients could tolerate the required

operative procedure and retain sufficient respira-tory function for normal life.

All resected specimens were referred to thedepartment of pathology in each institution.A pulmonary tumor was classified as a metastasisfrom the esophageal carcinoma based on histolog-ical findings such as; a similarity to the esophagealtumor; a tumor progression originating from thebronchial subepithelium; and/or a discontinuitybetween the tumor and the bronchial epithelium.Immunohistochemical examination was added toconfirm the digestive tract origin in 1 patient.

The prognostic factors examined in this studyincluded age, gender, UICC-TNM status of theprimary esophageal cancer, CEA or SCC level be-fore thoracotomy, DFI, initial recurrence site, his-tologically confirmed number and size ofmetastatictumors, operative procedure, residual tumor status,and adjuvant therapy before metastasectomy. Sur-vival time was calculated from the date of metasta-sectomy to death or most recent follow-up. Themedian follow-up period from metastasectomy was48.2 months (range, 26.1--214.5) for surviving pa-tients. Survival probability analyses were performedusing the Kaplan-Meier method and the differencesbetween groups were assessed by the log-lank testfor univariate analyses. To elucidate factors inde-pendently influencing survival, we performed mul-tivariate analyses of these variables using a forwardstepwise procedure according to the Cox’s propor-tional hazards model. The significance level usedfor adding and deleting a covariable from themodel was a 0.05 and 0.10 level of probability, re-spectively. All data were analyzed using the Statisti-cal Package for Social Sciences (SPSS Inc.,Chicago, IL). Statistical significance was assumedat a probability value <.05.

RESULTS

Patient baseline characteristics. Patient baselinecharacteristics are summarized in Table I. Therewere 19 men and 4 women, with a median age of66 years (range, 54--79) at the time of the pulmo-nary resection. Thirteen patients underwent trans-thoracic esophagectomy and 7 were treated withthe transhiatal approach. Of the 20 patients whounderwent esophagectomy, 19 patients hadcomplete resection (R0). The remaining patientunderwent gross complete resection that wasultimately diagnosed as a microscopically incom-plete resection (R1) because the margin of theproximal esophagus was positive for intraepithelialcancer spreading. This patient was enrolled in thisstudy because the primary tumor was well con-trolled without local recurrence. Five patients

Table I. Patient baseline characteristics

Variables No. of patients

Age at pulmonary resection (y)Median 66Range 54–79

GenderMale 19Female 4

Histopathologic typeSquamous cell carcinoma 21Adenocarcinoma 1Carcinosarcoma 1

Initial treatmentEsophagectomy 20Definitive chemoradiotherapy 3

Stage (UICC)I 2IIA/B 7III 8IVA/B 6

Neoadjuvant chemotherapybefore esophagectomy

Yes 4No 16

Adjuvant therapy after esophagectomyYes 9No 11

Initial recurrence sitePulmonary 19Extrapulmonary 4

DFI (mos)Median 15.5Range 3.8–79.1

DFI, Disease-free interval; UICC, International Union Against Cancer.

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with carcinoma of the upper or mid thoracicesophagus had cervical lymph node metastasisand were pathologically classified as having UICCstage IVA/B disease. Four patients received neoad-juvant chemotherapy consisting of 5-fluorouraciland cisplatin (FP) before esophagectomy. Adju-vant chemotherapy with the FP regimen or prophy-lactic radiotherapy to the mediastinum and/orsupraclavicular region was applied in 9 patients af-ter esophagectomy. Three patients received defini-tive CRT: 2 received 70 Gy of irradiation with FPand 1 received 60 Gy of irradiation with oraltegafur-uracil and cisplatin. A complete responsewas eventually achieved in all patients, accordingto the Response Evaluation Criteria in Solid Tu-mors.24 One patient with carcinoma of the midthoracic esophagus had celiac lymph node metas-tasis and was clinically classified as having UICCstage IVB disease.

Pulmonary metastases were detected on com-puted tomography scans in 20 patients and on

chest radiographs in the remaining 3 patients, withthe median DFI of 15.5 months (range, 3.8--79.1).Tumor marker (CEA or SCC) elevation beforethoracotomy was detected in 8 patients (35%).Cervical or mediastinal lymph node metastasespreceded pulmonary metastases in 4 patients.These extrapulmonary metastases were controlledby CRT and operative resection in 2 patients, CRTin 1, and radiotherapy alone in 1. DFI of these 4patients was calculated from the date of completecontrol of metastatic diseases to the diagnosis ofpulmonary metastasis.

Operative outcomes. Operative outcomes ofour study patients are shown in Table II. Twenty-four pulmonary metastasectomies were performedin 23 patients. Seven patients (30.4%) had multi-ple metastases with the maximum number of 4.One patient had bilateral pulmonary metastasesand underwent simultaneous bilateral wedge resec-tion using a video-assisted thoracic operation.Induction chemotherapy before metastasectomywith the FP regimen was administered to 5 pa-tients. Metastasectomy with chest wall resectionwas performed in 3 patients and resulted in R1resection in all cases. Two patients had pleuraldissemination at thoracotomy and underwent R2resection. The median operative time and bloodloss were 94.5 minutes (range, 48--300) and18 mL (range, 0--904), respectively. The medianlength of postoperative stay was 12.5 days (range,5--90). There was no postoperative in-hospital mor-tality. Postoperative complications occurred in 2(8.7%) patients: pneumonia in 1 and pyothoraxin another.

Recurrence pattern after pulmonary metasta-sectomy. Recurrent disease after pulmonary meta-stasectomy developed in 14 (66.7%) out of 21patients who underwent R0 or R1 resection. Themedian time to recurrence after the metastasec-tomy was 5.0 months (range, 1.0--21.8). Recurrentdisease developed in 8 patients (57.1%) within 6months and 12 patients (85.7%) within 12 months.Eleven patients had extrapulmonary recurrenceafter metastasectomy. Of these patients, 5 hadextrapulmonary recurrence alone, 3 had extrapul-monary followed by intrapulmonary recurrence,and 2 had synchronous recurrence of extra- andintrapulmonary lesions. The remaining 1 patientwho had initial recurrence in the remnant lungunderwent a second metastasectomy; however,lymph node metastasis developed 8 months laterand the patients died of the disease 22 months afterthe second metastasectomy. Five patients had >1extrapulmonary lesion, the sites of which were asfollows: lymph node (n = 7); pleura (n = 5); bone

Table II. Operative outcomes after pulmonarymetastasectomy

Variables No. of patients

LocationRight 11Left 11Bilateral 1

Tumor number1 162 4$3 3

Tumor size (mm)Median 15.0Range 5.0–45.0

ProcedureWedge resection (VATS) 17 (13)Segmentectomy 3Lobectomy 3

Residual tumor (UICC)R0 18R1 3R2 2

Postoperative complicationPneumonia 1Pyothorax 1None 21

UICC, International Union Against Cancer; VATS, video-assisted thoracicsurgery.

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(n = 4); liver (n = 1); and other sites (n = 5). Of 14patients with recurrent disease, 4 received radio-therapy, bronchial stenting, and spinal decompres-sion surgery with palliative intent. Symptomaticpalliation was successful in 3 of 4 patients withimprovement of pain, hemoptysis, or dyspnea.The remaining 10 patients received CRT, chemo-therapy alone, or radiotherapy alone for the meta-static disease with expectation of prolongedsurvival. The predicted 1-, 3-, and 5-year relapse-free survival rates after pulmonary metastasectomywere 42.9%, 33.3%, and 33.3%, respectively, with amedian relapse-free survival time of 8.7 months(range, 1.0--214.5; Fig 1, A).

Survival and prognostic factors. Six patientswere alive with no evidence of the recurrentdisease, and 2 were alive with the recurrent diseaseat the last follow-up. Thirteen patients died of therecurrent disease and 2 patients died of pneumo-nia, 1 with the recurrent disease and the other withno evidence of the disease. The predicted 1-, 3-,and 5- year overall survival rates after pulmonarymetastasectomy were 73.9%, 43.5%, and 43.5%,respectively, with a median survival time of 28.7months (range, 4.9--214.5; Fig 1, B).

A total of 13 variables were assessed to elucidatefactors influencing survival after pulmonary

metastasectomy (Table III). Of these variables, an-tecedent extrapulmonary metastasis was found tobe an unfavorable prognostic factor by univariateanalysis (P = 0.0411). The 3-year survival rate of19 patients who had pulmonary metastasis as theinitial recurrence was 54.7%; the 4 patients whohad extrapulmonary metastasis as the initial recur-rence did not survive >3 years after pulmonarymetastasectomy (Fig 2). Multivariate analyses, how-ever, failed to show the initial recurrence site tobe an independent prognostic factor (P = .0542;hazard ratio, 3.386; 95% confidence interval,0.978--11.72).

DISCUSSION

We previously reported that the recurrence rateafter radical esophagectomy was 43.3%, and me-dian survival time in patients with a hematogenousrecurrence was shorter than that in patients with alocal or lymph node recurrence (16 vs 25.5months, respectively).10 Nonoperative treatmentsare usually selected for hematogenous recurrencefrom esophageal carcinoma because it is widely re-garded as a systemic disease. Therefore, we con-ducted this case series study to elucidate theclinical significance of operative resection for me-tachronous pulmonary metastasis from esophagealcarcinoma.

The choice of operative procedure was depen-dent on tumor location, number, and size---theoperative options being wedge resection or ana-tomic resection, including segmentectomy andlobectomy. We generally avoided operative inter-ventions in esophageal cancer patients with pastsmoking history, prior thoracotomy, or radiationpneumonitis considering the remnant pulmonaryfunction reserve. Irrespective of approach, lowpostoperative complications and no in-hospitalmortality indicate that pulmonary metastasectomyis a safe and feasible treatment even in patientsafter radical esophagectomy.

The principles for operative resection of meta-static lung tumors proposed by Thomford et al in196513 excludedpatients with bilateral intrathoraciclesions and/or extrathoracic lesions. One patientwith bilateral metastases and 4 with antecedentlymph node metastases, however, were eligible forpulmonary metastasectomy in the present series.The recent trend to expand the principles ofThomford et al has led to aggressive pulmonarymetastasectomy based on the survival benefit.McCormack et al15 reported that the 5- and 10-yearsurvival rates in patients with solitary metastasesfromcolorectal carcinomadidnot differ significantlyfrom patients with multiple metastases in the

Fig 1. Kaplan-Meier estimate of relapse-free survival in 21 patients who underwent R0 or R1 resection (A) and that ofoverall survival in 23 patients eligible for pulmonary metastasectomy (B).

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ipsilateral or bilateral lung. For extrathoracic lesions,especially livermetastasis from colorectal carcinoma,very few authors reported that pulmonary metasta-sectomy in patients who had previously receivedliver metastasectomy was contraindicated.14-19

Shiono et al22 retrospectively reviewed the regis-try in the Metastatic Lung Tumor Study Group ofJapan and reported that the 5-year survival rate af-ter pulmonary metastasectomy was 29.6%, with amedian survival time of 18 months in 49 patientswith pulmonary metastasis from esophageal carci-noma. In our series, the 5-year survival rate andmedian survival time were 43.5% and 28.7 months,respectively. Factors that caused the difference insurvival between the 2 series are uncertain. In theShiono et al multi-institutional study, however,not all the patient records from the registry wereanalyzed in detail and the methods used to distin-guish metastatic tumors from primary lung cancerwere not clearly described. The possibility thatsome patients with primary lung cancer were in-cluded in their study population was not fullyexcluded. The recurrence rate after pulmonarymetastasectomy was 33% in their study and 67%in the present study. The median relapse-free inter-val time of our 21 patients who underwent R0 orR1 resection was 8.7 months, which was extremelyshort compared with the median overall survivaltime of 28.7 months. This major discrepancy maybe attributed to the treatment for recurrent dis-ease after pulmonary metastasectomy. Althoughwe treated with palliative intent, it might havehad some impact on the prolonged survival.

The prognosis of patients who underwent non-operative treatment for pulmonary metastasis wasalso unclear. In the Niigata University Medical andDental Hospital, 28 patients were diagnosed withmetachronous pulmonary metastasis and under-went chemotherapy or best supportive care during

the same period as that of our present study. Forthese patients, the median survival time after thedetection of pulmonary metastasis was 5.4 months(range, 0.2--31.2; unpublished data). Therefore,operative resection for pulmonary metastasis fromesophageal carcinoma seems to be an acceptabletreatment of choice; however, we should take aconstitutional selection bias into considerationbetween patients who underwent operative andnonoperative treatment.

Furthermore, stereotactic radiosurgery is cur-rently evaluated for the treatment of metastaticpulmonary tumors. Rusthoven et al25 reported aphase I/II trial of stereotactic radiosurgery forthe treatment of 38 patients with 1--3 pulmonarymetastases. Local control at 1 and 2 years was100% and 96%, respectively, whereas distant pro-gression occurred in 63% of patients with medianprogression-free survival of 8.4 months. Mediansurvival time and 2-year survival rates were 19months and 39%, respectively, which were worsethan those with operative intervention in thisstudy. Because the study included patients with var-ious types of primary tumors and extrathoracicrecurrence, these results should not be simplycompared with ours. Stereotactic radiosurgerymay be a promising treatment modality for thosepatients who are not suitable for operative inter-vention, considering its good local control.

We showed that the initial recurrence site wasthe only significant prognostic factor after pulmo-nary resection. The presence of extrapulmonarymetastases before the detection of pulmonarymetastases was the unfavorable prognostic factor.We believe that pulmonary resection should not beperformed for patients with extrapulmonary me-tastases even if the disease is well controlled byvarious treatments. The International Registry ofLung Metastases was established in 1991 and

Table III. Survival and univariate analysis ofprognostic factors after pulmonary metastasectomy

VariablesNo. ofpatients

5-yearsurvival(%)

MST(mos)

Pvalue

Age (yrs)$66 12 37.5 28.7 .5885<66 11 54.6 82.0

GenderMale 19 42.1 28.3 .9837Female 4 50.0 31.4

UICC-T*T1/2 6 66.7 63.0 .3595T3/4 17 28.3 33.6

UICC-N*N0 10 56.0 82.0 .5024N1 13 35.2 35.2

UICC-M*M0 17 53.5 63.0 .1832M1a/b 6 16.7 6.5

Initial recurrence sitePulmonary 19 54.7 63.0 .0411Extrapulmonary 4 0 11.0

DFI (mos)$15 12 41.7 28.7 .6559<15 11 47.7 27.9

TM (CEA or SCC)before thoracotomy

Elevated 8 33.3 19.0 .2196Within normalrange

15 48.9 28.7

Tumor numberSolitary 16 46.9 28.3 .7231Multiple 7 35.7 31.4

Tumor size (mm)$15 14 28.6 19.0 .0746<15 9 71.1 82.0

Operative procedureWedge resection 17 44.1 31.4 .6775Anatomic resectiony 6 41.7 28.3

Residual tumor (UICC)R0 18 44.4 28.7 .7189R1/2 5 40.0 31.4

Induction chemotherapybeforemetastasectomy

Yes 5 30.0 28.7 .5970No 18 46.7 31.4

*UICC tumor node metastasis (TNM) was classified for primary esoph-ageal carcinoma.yAnatomic resection included segmentectomy and lobectomy.

CEA, Carcinoembryonic antigen; DFI, disease-free interval; MST, mediansurvival time; SCC, squamous cell carcinoma antigen; TM, tumor marker;UICC, International Union Against Cancer.

Fig 2. Kaplan-Meier estimate of survival according to theinitial recurrence site (pulmonary versus extrapulmo-nary; P = .0411).

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accrued 5,206 patients of lung metastasectomy.26

The registry authors noted that complete resec-tion, long DFI, and single lesions were favorablemeasurements for long-term survival when

different tumor types were included. Some authorsreported that prethoracotomy CEA elevation was aprognostic factor in pulmonary metastasis from co-lorectal carcinoma.20 In our study, the 5-year sur-vival rate in patients with normal CEA or SCClevel was better than that in patients with elevatedCEA or SCC level. These prognostic factors werenot correlated with survival after metastasectomyin our series. These different results may be par-tially attributed to the small number of patientsin a retrospective study and the difference in onco-logic behavior of esophageal carcinoma from theother malignant tumors such as colorectalcarcinoma.

For esophageal carcinoma, Shiono et al22 re-cently showed that the DFI was a significant prog-nostic factor using multivariate analysis. Becausethe median DFI was 15.5 months in our series,we compared the survival of patients with a DFIof $15 months with those with a DFI of <15months; however, there was no significant differ-ence (P = .6559). For a more accurate analysis,an accumulation of patients who underwent pul-monary resection for metachronous metastasisfrom esophageal carcinoma is necessary. Further-more, to clarify the effect of operative resectionon patient survival, a prospective randomized con-trol trial comparing operative resection with non-operative treatment should be conducted.

Our survival data were superior to the previousreports of survival after a recurrence after radicalesophagectomy.10 The major discrepancy is mainlyattributed to meticulous patient selection. In addi-tion, not only pulmonary metastasectomy but alsothe other additional treatments might influence

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the prolonged survival. It’s not known whether ourresults may similarly apply to pulmonary metastasisfrom esophageal adenocarcinoma, which is thepredominant histology in the Western countries.There is no clear evidence supporting in our studybecause the majority of the primary tumor histol-ogy was SCC in this study. Nonetheless, our resultssuggest that a favorable outcome can be expectedin the selected patients and that operative inter-vention has the potential to cure pulmonary metas-tasis from esophageal carcinoma.

In conclusion, we believe now that operativeintervention for metachronous pulmonary metas-tasis from esophageal carcinoma is acceptable.Because antecedent extrapulmonary metastasiswas found to be an unfavorable prognostic factorin this series, operative resection is not recom-mended for such patients.

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