90 Postoperative chemotherapy药理药效研究 动物模型

Postoperative chemotherapy vs.chemoradiotherapy for thoracic esophageal cancer:a prospective randomized clinical trialM.T achibana,H.Y oshimura,S.Kinugasa,M.Shibakita,D.K.Dhar,S.Ueda,T .Fujii and N.NagasueDepartment of Digestive and General Surgery,Shimane Medical University,Enya-cho 89-1,Izumo 693-8501,Shimane,JapanBackground:Neither postoperative radiotherapy nor chemotherapy alone provided a survival benefit after curative esophagectomy for esophageal squamous carcinoma.Material and methods:Of 103consecutive patients who underwent potentially curative esophagectomy for esophageal squamous carcinoma,45patients with advanced cancers without preoperative adjuvant treatments were prospectively randomized to two groups;postoperative chemotherapy alone (Group A,n ¼23)and postoperative radio/chemotherapy (Group B,n ¼22).In Group A,cisplatin (CDDP)(50mg/m 2)was given by intravenous infusion on days 1and 15,and 5-fluorouracil (5-FU)(300mg/m 2)was given daily by continuous intravenous infusion for 5weeks.In Group B,in addition to the same chemotherapeutic regimen of Group A,50Gy of radiotherapy was given to the mediastinum over 5weeks.The immunohistochemical staining of tumoral p53and microvessel density was undertaken to correlate to the radio/chemosensitivity.Results:There were no significant differences in the clinicopathologic characteristics between the two groups.The median dose of 5-FU and CDDP administered were not significantly different between the two groups.The mean (SD)dose of radiotherapy in Group B was 42þ10Gy.The 1-,3-and 5-year survival rates in Group A were 100,63and 38%and those in Group B were 80,58and 50%,respectively ðP ¼0:97Þ:In each group,four patients succumbed to locoregional recurrences.T umoral p53was immunohistochemically negative in 43%in Group A and 77%in Group B ðP ¼0:03Þ;indicating that many patients in Group B might be potentially sensitive to radiochemotherapy.The 3-and 5-year survival rates (75and 64%)of patients with p53negative expression ðn ¼18Þwere significantly ðP ¼0:03Þbetter than those with p53positive expression (n ¼27;44and 26%).The long-term survival was better for patients with p53negative tumours than those with p53positive tumours in Group B (P ¼0:06by long-rank test,P ,0:05by Generalized-Wilcoxon test).However,the long-term survival was not different between the patients who had p53negative and positive tumours in Group A ðP ¼0:19Þ:These data suggest that there were no survival advantage for patients receiving radiotherapy in Group B,instead p53negative tumours appeared to have a favorable prognosis.Conclusion:Postoperative radiotherapy administered concurrently with chemotherapy does not provide a survival benefit compared with chemotherapy alone.T umoral p53expression has a predictive value for survival in patients treated with postoperative radio/chemotherapy.q 2003Elsevier Ltd.All rights reserved.Key words:esophageal cancer;adjuvant therapy;chemotherapy;radiotherapy;long-term prognosis.INTRODUCTIONRecent advances in early diagnosis and meticulous lymphadenectomy have made esophageal carcinoma a potentially curable disease when diagnosed at an earlystage.1,2Long-term survival remains,however,disap-pointing when the disease extends through the esopha-geal wall or when tumour is extensive lymph nodes involvement.3,4Three-field extensive lymph node dissec-tion during esophagectomy has become a standard surgical procedure to obtain an accurate pathological staging and to improve surgical results in Japan,5–8and this technique is now widely practice in Western countries.9,10The long-term outcomes following suchEJSO 2003;29:580–587doi:10.1016/S0748-7983(03)00111-20748–7983/03/$30.00q 2003Elsevier Ltd.All rights reserved.Correspondence to:Dr M.T achibana,Department of Digestive and General Surgery,Shimane Medical University,Enya-cho 89-1,Izumo 693-8501,Shimane,Japan.T el.:þ81-853-20-2232;Fax:þ81-853-20-2229;E-mail:nigeka35@shimane-med.ac.jpextended esophagectomies are not necessarily satisfac-tory and its application is limited by the ability of patients to tolerate the surgical stress.5–8Radiotherapy and/or chemotherapy have been used as adjuvant treatments before and/or after esophageal resection in an attempt to improve the long-term survival of patients after esophagectomy.11,12Random-ized controlled trials have shown no benefit for either postoperative radiotherapy alone13–15or postoperative chemotherapy alone.16–18However,there has been no randomized study evaluating concurrent postoperative radiotherapy and chemotherapy.Therefore,we designed and conducted this prospective randomized trial com-paring postoperative chemotherapy alone and chemor-adiotherapy after curative resection for squamous cell carcinoma of the thoracic esophagus.Moreover,expression of mutant p53and high microvessel density(MVD)(angiogenesis)may be an important determinant of tumour resistance to che-motherapy and/or radiotherapy mainly by attenuating apoptosis.19In esophageal carcinoma,the mutational status of p53protein20or degree of MVD21have been reported to be predictive of chemoradiosensitivity.We therefore investigated p53expression and MVD in the present study.PATIENTS AND METHODSBetween November1991and December2000,103 (69.1%)out of149patients with primary squamous cell carcinoma of the thoracic esophagus underwent R022 esophagectomy at the Department of Digestive and General Surgery,Shimane Medical University.Among those103patients,eight received preoperative radio/ chemotherapy because of locally advanced(T4)disease, 41did not receive any adjuvant treatment due to superficial tumours(T1)without lymph nodes metas-tases in35and postoperative complications in six.Nine patients received miscellaneous postoperative adjuvant treatments off protocol,and,therefore,the remaining45 patients were enrolled in this study.One month after surgery,the45patients were randomized to two groups.Forty-five patients enrolled in this study were selected according to the eligibility criteria;(1)age under80years old,(2)Karnofsky performance status0–3,(3)R022 esophagectomy according to the pathological examin-ation of the resected specimens,(4)adequate bone marrow,renal,and hepatic function;(white blood cell .4000/mm3,platelet.100000/mm3,hemoglobin .10g/dl,24h creatinine clearance(24hrCCr).50ml/ min,serum creatinine,1.5mg/dl,AST,100IU/l, ALT,100IU/l,total-bilirubin,1.5mg/dl).Informed consent was obtained from all patients before treatment.All of those patients underwent a right transthoracic subtotal esophagectomy along with a three-field lymph node dissection including the cervical(bilateral supracla-vicular regions),mediastinal(periesophagus and around the trachea including around both recurrent laryngeal nerves),and abdominal(perigastric region and around the celiac axis)lymph nodes.Reconstruction was usually carried out with a gastric tube through the retrosternal route and esophagogastrostomy was performed in the neck under cervical incision and facilitated by laparotomy.Those45patients were prospectively randomly assigned either to two groups:postoperative chemother-apy alone(Group A,n¼23)and postoperative radio-chemotherapy(Group B,n¼22).Selection was performed before starting treatments within2months after the operation.In Group A,cisplatin(CDDP) (50mg/m2)was given by intravenous infusion on days1 and15and5-fluorouracil(5-FU)(300mg/m2)was daily given by continuous intravenous infusion for5weeks. Group B received the same chemotherapy regimen as Group A,with the addition to45–50Gy radiotherapy given to the tumour bed with at least2cm margin.The dose was2.0Gy/dayfive times per week for4–5weeks. Immunohistochemical detection of p53 expression and microvessel density (MVD)Paraffin-embedded sections of esophageal tumours were deparaffinized in xylene and rehydrated in graded ethanol.The sections were boiled at1218C by autoclave in10mM sodium citrate(pH 6.0)for20min and incubated in H2O2(3%)for30min.The slides were then washed with phosphate-buffered saline(PBS)three times for5min.After treatment with blocking serum for 30min,the sections were incubated with the primary antibodies(1:50dilution for14h).Mouse monoclonal antibodies against p53and CD34(Santa Cruz Biochem-istry Inc.,Santa Cruz,CA)were used in this study.The immunohistochemical staining was done using the Streptoavidin-biotin(SAB)kit(Nichirei,T okyo,Japan) by the avidin–biotin-peroxidase method,according to the manufacture’s instructions.Aminoethylcalbasol (AEC)was used as the chromogen,and the slides were counterstained with hematoxylin.Sections without primary antibodies as well as those with non-immunized mouse serum were served as negative controls.All histological slides were examined by two observers(M.S. and M.T.)who were unaware of the clinical data or the disease outcome.When the interpretation differed between the two observers,re-evaluation was done for afinal decision on a conference microscope. Evaluation of p53expression and MVD Extent of p53expression was evaluated by staining. Negative staining was defined as less than one-third of the tumour cells being stained,and positive staining was defined as more than one-third of tumour cells being stained.CHEMOTHERAPY FOR RESECTABLE ESOPHAGEAL CANCER581The areas of tumour with the most extensive neovascularization were identified by scanning at least three different microscopic slides at low power (100£).23The numbers of microvessels per200£microscopicfield were counted.At leastfive different 200£fields were evaluated for each case,to obtain the mean microvessel density for each patient.Only micro-vessels that contained a positively stained endothelial cell or endothelial cell cluster,either with or without a lumen,or with or without red blood cells,and were clearly separate from other microvessels and mesen-chymal tissue elements,were considered a single microvessel.Statistical analysesClinicopathologic characteristics were investigated according to the TNM staging system of the International Union Against Cancer(UICC).22Adverse effects of adjuvant treatments were classified according to the reporting results of cancer treatment.24The patients were regularly followed at the outpatient department monthly interval untilfirst postoperative year and later3 months interval untilfifth year.The patients were checked for recurrence regularly with3months interval by blood examination and with6months interval by chest X-ray,abdominal ultrasonography and computed tomography.The outcome of patients was examined and those who clearly died of recurrences were regarded as tumour-related deaths.The survival rates were esti-mated by the Kaplan–Meier method25and the patients who survived more than5years after the operation were regarded as being cured.The statistical analysis was carried out by the log-rank test to test for equality of the survival curves.Statistical differences were analyzed by the standard chi-square test with or without Yates’correction and unpaired t-test.The level of significance was p,0:05:RESUL TSClinicopathologic background Clinicopathologic characteristics of both groups are shown in T able1.There were no significant differences between the two groups regarding gender,age,tumour location,tumour size and histological type.pT,pN,pM, and pStage were also not significantly different between Group A and Group B.Distant lymph node metastases (Mlym)were found in seven patients(30%)in Group A and eight(36%)in Group B.Dose of adjuvant treatments appliedT wenty patients(87%)received full dose of CDDP in Group A and17(77%)in Group B.The mean(SD)dose of CDDP received was139^30mg in Group A and 135^39mg in Group B,without a significant difference between the two groups.The range of CDDP was70–170mg in Group A and50–200mg in Group B.In Group A,three patients received reduced dose of CDDP;renal failure induced byfirst administration of CDDP,deterio-rated24hrCCr and patient’s refusal because of severe nausea in one each.In Group B,five patients received reduced dosages of CDDP;worsened24hrCCr in two, stomatitis in one and patients’refusal for severe nausea and malaise in two,respectively.Only10patients(43%)received the full dose of5-FU in Group A and the remaining13patients received variable reduced dosages of5-FU due to miscellaneous adverse effects.Likewise,14patients(64%)received the full dose of5-FU in Group B and another eight patients received reduced dosages of5-FU.The median(SD)dose of5-FU(%)was9545^5136mg in Group A,ranging 450–17500mg and was12124^5444mg in Group B, ranging from400to20700mg;not significantly different between the two groups.Full doses of radiotherapy were given in20patients (91%)in Group B and the mean(SD)dose was42^10 Gy,ranging from14.4to55Gy.T wo patients received reduced dose of radiotherapy because of prolonged leukocytopenia in one and severe appetite loss with malaise in one.Adverse effectsGrade3and grade4adverse effects were found in Group A;decreased hemoglobin levelðn¼1Þ;thrombocytope-niaðn¼2Þ;elevated BUN/Cr level or decreased 24hrCCr levelðn¼2Þ;and diarrheaðn¼2Þ:Adverse effects seen in Group B were leukocytopeniaðn¼2Þand stomatitisðn¼1Þ:There were no statistical differences in the incidence of adverse effects between the two groups,indicating that radiotherapy concurrent with chemotherapy did not increase adverse effects(T able2). Long-term survivalMedian follow-up was35months(ranging4–112 months).The1-,3-and5-year overall survival rates of all45patients were91,60and45%,respectively.The1-, 3-and5-year survival rates in Group A were100,63and 38%and those in Group B were80,58and50%, respectively.The median survival time for Group A was 28months and that for Group B was31months.There was no statistical difference in survival between the two groupsðP¼0:97Þ(Fig.1(A)).In stratification of node positive patients(pN1,n¼34),the1-,3-and5-year survival rates in Group A were94,47and47%and those in Group B were77,41and31%,respectively;these results were not significantly different(P¼0:55;Fig. 1(B)).In the subgroup with pT2and pT3tumoursðn¼37Þ;the1-,3-and5-year survival rates in Group A wereM.TACHIBANA ET AL.58295,56and35%,respectively,and those in Group B were 86,47and47%;showing no statistical differenceðP¼0:86Þ:Outcome and pattern of recurrenceEight patients(35%)died of recurrent esophageal disease in Group A and nine(41%)succumbed to disease in Group B.In Group A,four patients died mainly of locoregional recurrence and four died from disseminated disease.In Group B,four patients succumbed mainly to locoregional recurrences andfive succumbed to wide-spread metastases(T able3).T wo patients in Group A died of pneumonia at13months postoperatively and of cerebrovascular attack at37months and one patient in Group B succumbed to gastric ulcer perforation at7 months postoperatively.There were no significant differences between the two groups,indicating that radiotherapy did not reduce locoregional recurrence. P53expression and MVD in each group and its long-term survivalOnly10tumours(43%)showed negative mutant p53T able1Clinicopathological features of patients in each groupVariable Group Aðn¼23ÞGroup Bðn¼22Þp Value GenderMale21(91)20(91)Female2(9)2(9)NS(0.68) Age(years),608(35)10(45)$60,,6913(56)6(27)NS(0.09) $702(9)6(27)Mean^SD61.2^7.961.2^9.0T umour locationUpper3(13)5(23)Middle10(43)11(50)NS(0.47) Lower10(43)6(27)T umour size(cm)Range 2.0–9.00.9–11.0Mean^SD 5.1^2.0 4.4^2.3NS(0.28) Histological typeWell7(30)13(59)Moderately10(44)6(27)NS(0.12) Poorly3(13)3(14)Others3(13)0Depth of invasion(pT)pT13(13)3(14)pT211(48)11(50)NS(0.98) pT3,T49(39)8(36)Lymph node metastasis(pN)N05(22)6(28)N118(78)16(72)NS(0.93) Distant metastasis(pM)M016(70)14(64)M1(lym)7(30)8(36)NS(0.92) pStageI01(4)IIA5(22)5(23)NS(0.64) IIB3(13)4(18)III8(35)4(18)IV7(30)8(37)Numbers in parentheses are percentage.NS;not significant.CHEMOTHERAPY FOR RESECTABLE ESOPHAGEAL CANCER583expression in Group A,whereas17patients(77%) showed negative p53expression in Group BðP¼0:03Þ: Median MVD was39ranging17–111.Fourteen tumours (61%)expressed low MVD in Group A,whereas10 tumours(45%)did in Group BðP¼0:38Þ:These data suggested that there were many patients in Group B who could be potentially sensitive to radiotherapy and/or chemotherapy.In terms of long-term survival according to p53expression,the3-and5-year survival rates of patients with p53negative expressionðn¼18Þwere75and64%, respectively,and those with p53positive expressionðn¼27Þwere44and26%;showing statistical difference (P¼0:03;Fig.2(A)).The long-term survival was better for patients with p53negative tumours than that for patients with p53positive tumours in Group B(P¼0:06 by long-rank test,P,0:05by Generalized-Wilcoxon test).However,the long-term survival was not different between the patients who had p53negative and positive tumours in Group AðP¼0:19Þ:According to MVD,the long-term survivals between MVD low and MVD high expression were not significantly different(P¼0:90;Fig. 2(B)).These data suggested that no survival advantage was found in Group B compared with Group A,although there could have been more potentially radiosensitive cases in Group B.DISCUSSIONIn a previous preliminary study conducted in our institution,randomization of pre-and postoperative radio/chemotherapy vs.postoperative radio/chemother-apy after curative esophagectomy for esophageal cancer was performed(unpublished data).This study showed no survival differences between the two groups and,there-fore,encouraged us to compare postoperative che-motherapy alone with chemo/radiotherapy.We were not unable to conduct a study that included a surgery alone in the present study because of the peculiarity of the Japanese national medical insurance system.Because this system covers almost all medical payments,the majority of Japanese patients want to receive multiple treatments without consideration of medical costs,thus,it is difficult to obtain an informed consent for a surgery alone arm when we conducted this study at the beginning of1990s. We might be criticized that the patients’number of each group in this study might be too small to draw a meaningful conclusion.We intended to receive more patients in each armðn¼40Þto make the analysis more powerful at the beginning of this study.The preliminary intermediate analysis,however,showed that there was no survival advantage between the two groups,thus causing us to stop this study at this point.The standard dose of chemotherapy applied in the present study was relatively low compared with the usual dosages seen in the Westerns.17,26,27Using compara-tively low dosages of chemotherapy in the present study, 22%of patients received reduced dose of CDDP and the average dose(%)of5-FU was only74%due to various adverse effects.The dose of chemotherapy used in the present study is consistent with that currently used in Japanese patients.16,18There was no statistically significant difference in survival between the postoperative radio/chemotherapy and chemotherapy groups,even with stratification of pNT able2Adverse effects of adjuvant treatments in each groupVariable Grade p Value234WBCGroup A600B1120NS HemoglobinGroup A010B000NS PlateletsGroup A011B000NS BUN/Creatinine or24hrCCrGroup A320B300NS DiarrheaGroup A002B000NS StomatitisGroup A400B410NS Appetite loss or vomitingGroup A551B640NS OthersGroup A200B200NS 24hrCCr,24h creatinine clearance;NS,not significant.T able3Clinical outcomes and pattern of recurrence in each groupGroup A Group B p Value Alive1312Dead1010Died of disease89 Locoregional recurrence44Visceral recurrence45Died without disease21NS(0.80) NS,not significant.M.TACHIBANA ET AL.584and pT for stage.Three randomized controlled trials 13–15compared esophagectomy alone with esopha-geal resection plus postoperative radiotherapy of 43–56Gy.None of those studies found any survival benefit of adjuvant postoperative radiotherapy compared with surgery alone.Moreover,in Group B in the present study,four patients (14%)developed and died of local recurrences.Based on those data,we conclude that postoperative radiotherapy even if administered concur-rently with chemotherapy is neither effective in control-ling locoregional recurrence nor in improving survival after potentially curative resection for esophageal cancer.Radiotherapy for esophageal cancer should,therefore,be only used for carefully selected cases for control of bony pain from bone metastases and/or of hydrocephalus due to brain metastases.28Since the same clinicopathologic modalities existed between Group A and Group B,there were many patients in Group B who could have been potentially sensitive to chemoradiotherapy due to high incidence of mutant p53negative expression.Certainly the long-term prognosis of the patients with mutant p53negative expression was better than those who have p53positive.Although there were significantly more p53negative cases with a favorable prognosis in Group B,no survival difference was found between Group A and Group B.Lowe et al .19showed that mutant p53expressing tumours could be resistant to radiotherapy and/or chemotherapy mainly by the attenuation of apoptosis.In esophageal carcinoma,the mutational status of p53protein 20is predictive of chemo-and/or radiosensitivity.From the viewpoint of molecular biological results,even if adjuvant radiotherapy was administered for cases with mutant p53negative expression,radiotherapy was not effective.These data may lead to conclude that radio-therapy should be abandoned for adjuvanttreatmentFigure 1Survival curves between the chemotherapy group (Group A,n ¼23)and radiochemotherapy group (Group B,n ¼22).The 1-,3-and 5-year survival rates in Group A were 100,63and 38%,respectively,and those in Group B were 80,58and 50%,showing no statistical difference (P ¼0:97;1A).In stratification of node positive patients (pN1,n ¼34),the 1-,3-and 5-year survival rates in Group A were 94,47and 47%,respectively,and those in Group B were 77,41and 31%;not significantly different (P ¼0:55;1B).CHEMOTHERAPY FOR RESECTABLE ESOPHAGEAL CANCER 585after curative esophagectomy even if administered with chemotherapy.For future development in the multimodal treatment for resectable esophageal cancer,newer sophisticated modalities should be sought.Ancona et al .29and Law et al .26reported that neoadjuvant chemotherapy,using high-dose CDDP and intensive 5-FU,for advanced esophageal tumours increased the resection rate and improved the overall long-term survival particularly for responders.In esophageal adenocarcinoma (not squa-mous carcinoma),one randomized study showed that preoperative radiochemotherapy (using high-dose CDDP and intensive 5-FU)followed by surgery yielded a survival benefit compared to surgery alone.30There is also a need for accurate criteria that can predict responders and non-responders before treat-ment.Measures are needed to increase the effect on local recurrences such as increasing dose intensity and using newer drugs.T aken together,inclusion of high-dose CDDP and intensive 5-FU in the preoperative chemo-therapy regimen may bring a more fruitful result in future studies.In conclusion,in the present study postoperative radiotherapy administered concurrently with che-motherapy does not confer a survival benefit compared to chemotherapy alone.T umoral p53expression has a predictive value for survival in patients treated with postoperative radio/chemotherapy.REFERENCES1.T achibana M,Y oshimura H,Kinugasa S,Hashimoto N,Dhar DK,Abe S,et al.Clinicopathological features of superficial squamous cell carcinoma of the esophagus.Am J Surg 1997;174:49–53.2.T achibana M,Kinugasa S,Dhar DK,T abara H,Masunaga R,Kotoh T .Prognostic factors in T1and T2squamous cell carcinoma of the thoracic esophagus.Arch Surg 1999;134:50–4.3.Iizuka T ,Isono K,Kakegawa T ,Watanabe H.Parameters linked to ten-year survival in Japan of resected esophageal carcinoma.Chest 1989;96:1005–11.Figure 2Survival curves according to p53expression and MVD.The 3-and 5-year survival rates of p53negative cases ðn ¼18Þwere 75and 64%,respectively,and those of p53positive cases ðn ¼27Þwere 44and 26%(P ¼0:03;2A).There was no survival difference between MVD low and high group (2B).M.TACHIBANA ET AL .5864.Daly JM,Karnell LH,Menck HR.National cancer data base reporton esophageal carcinoma.Cancer1996;78:1820–8.5.T achibana M,Kinugasa S,Dhar DK,Kotoh T,Shibakita M,Satoshi O.Prognostic factors after extended esophagectomy for squamous cell carcinoma of the thoracic esophagus.J Surg Oncol1999;72: 88–93.6.Akiyama H,Tsurumaru M,Udagawa H,Kajiyama Y.Radical lymphnode dissection for cancer of the thoracic esophagus.Ann Surg 1994;220:364–73.7.Nishimaki T,Suzuki T,Suzuki S,Kuwabara S,Hatakeyama K.Outcomes of extended radical esophagectomy for thoracic esophageal cancer.J Am Coll Surg1998;186:306–12.8.Fujita H,Kakegawa T,Yamana H,Shima I,T oh Y,T omita Y.Mortalityand morbidity rates,postoperative course,quality of life,and prognosis after extended radical lymphadenectomy for radical lymphadenectomy for esophageal cancer.Ann Surg1995;222: 654–62.9.Altorki NK,Skinner DB.Occult cervical nodal metastasis inesophageal cancer:preliminary results of three-field lymphade-nectomy.J Thorac Cardiovasc Surg1997;113:540–4.10.Lerut T,Leyn PD,Coosemans W,Raemdonck DV,Scheys I,SaffreEL.Surgical strategies in esophageal carcinoma with emphasis on radical lymphadenectomy.Ann Surg1992;216:583–90.11.Bosset JF,Gignoux M,T riboulet JP,Tiret E,Mantion G,Elias D.Chemoradiotherapy followed by surgery compared with surgery alone in squamous cell cancer of the esophagus.N Engl J Med1997;337:161–7.12.Geh JI,Crellin AM,Glynne-Jones R.Preoperative(neoadjuvant)chemoradiotherapy in oesophageal cancer.Br J Surg2001;88: 338–56.13.T eniere P,Hay JM,Fingerhut A,Fagniez PF.Postoperative radiationtherapy does not increase survival after curative resection for squamous cell carcinoma of the middle and lower esophagus as shown by a multicenter controlled trial.French university association for surgical research.Surg Gynecol Obstet1991;123–30.14.Fok M,Sham JST,Choy D,Cheng SWK,Wong J.Postoperativeradiotherapy for carcinoma of the esophagus:a prospective, randomized controlled study.Surgery1993;113:138–47.15.Zieren HU,Mueller JM,Jacobi CA,Pichlmaier H,Mueller RP,StaarS.Adjuvant postoperative radiation therapy after curative resection of squamous cell carcinoma of the thoracic esophagus:a prospective randomized study.World J Surg1995;19:444–9. 16.Japanese esophageal oncology group,A comparison of chemother-apy and radiotherapy as adjuvant treatment to surgery for esophageal carcinoma.Chest1993;104:203–7.17.Pouliquen X,Levard H,Hay JM,McGee K,Fingerhut A,Zantin OL.French associations for surgical research:5-fluorouracil and cisplatin therapy after palliative surgical resection of squamous cell carcinoma of the esophagus;a multicenter randomized trial.Ann Surg1996;223:127–33.18.Ando N,Iizuka T,Kakegawa T,Isono K,Watanabe H,Ide H.Arandomized trial of surgery with and without chemotherapy for localized squamous carcinoma of the thoracic esophagus:the Japan clinical oncology group study.J Thorac Cardiovasc Surg1997;114: 205–9.19.Lowe SW,Bodis S,McClatchey A,Remington L,Ruley HE,FisherDE.p53Status and the efficacy of cancer therapy in vivo.Science 1994;266:807–10.20.Nabeya Y,Loganzo F Jr.,Maslak P,Lai L,Oliveira AR,Schwartz GK.The mutational status of p53protein in gastric and esophageal adenocarcinoma cell lines predicts sensitivity to chemotherapeutic agents.Int J Cancer1995;64:37–46.21.T orres C,Wang H,T urner J,Shahsafaei A,Odze R.Prognosticsignificance and effect of chemoradiotherapy on microvessel density(angiogenesis)in esophageal Barrett’s esophagus-associated adenocarcinoma and squamous cell carcinoma.Hum Pathol1999;30:753–8.22.UICC staff,TNM Classification of Malignant Tumours,5th edn.NewY ork:Willy-Liss,1997.23.Weidner N,Semple J,Welch WR,Folkman J.T umor angiogenesisand metastasis—correlation in invasive breast carcinoma.N Engl J Med1991;324:1–8.ler AB,Hoogstraten B,Staquet M,Winker A.Reporting resultsof cancer treatment.Cancer1981;47:207–14.25.Kaplan EL,Meier P.Non-parametric estimation for incompleteobservations.J Am Stat Assoc1958;53:457–81.w S,Fok M,Chow S,Chu KM,Wong J.Preoperativechemotherapy versus surgical therapy alone for squamous cell carcinoma of the esophagus:a prospective randomized trial.J Thorac Cardiovasc Surg1997;114:210–7.27.Kelsen DP,Ginsberg R,Pajak TF,Sheahan DG,Gunderson L,Mortimer J.Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer.N Engl J Med1998;339:1979–84.28.Lehnert T.Multimodal therapy for squamous carcinoma of theoesophagus.Br J Surg1999;86:727–39.29.Ancona E,Ruol A,Castoro C,Chiarion-Sileni V,Merigliano S,SantiS.Fist-line chemotherapy improves the resection rate and long-term survival of locally advanced(T4,anyN,M0)squamous cell carcinoma of the thoracic esophagus:final report on163 consecutive patients with5-year follow-up.Ann Surg1997;226: 714–24.30.Walsh TN,Noonan N,Hollywood D,Kelly A,Keeling N,HennessyTPJ.A comparison of multimodal therapy and surgery for esophageal adenocarcinoma.N Engl J Med1996;335:462–7. Accepted for publication9June2003CHEMOTHERAPY FOR RESECTABLE ESOPHAGEAL CANCER587。