Ambrosi, A.

claudio belluco

Farinati, F.

Lise, M.

Marchet, A.

Mencarelli, R.

Nitti, D.

Olivieri, M.

English

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34IntroductionThe main treatment modality for gastric carcinoma, whichis still the second most common cause of cancer-related de-aths worldwide, is surgery. In Western countries, a radicalsurgical procedure can be achieved in 70-80% of cases witha survival at 5 years of 35-40%1-3. However, even after radi-cal procedures, recurrences occur in 50-60% of cases4. Pa-tients with relapse mainly present distant metastasis, but in20- 40% of cases, recurrences are loco-regional and involvethe “gastric bed”, the lymph nodes and/or the anastomosisor the duodenal stump4. Loco-regional recurrences are pro-bably related to the biological characteristics of the tumorbut, in some cases, they may be due to an inadequate surgi-cal procedure.The results reported by Japanese surgeons are better thanthose reported in Western countries for all disease stages,with a 5-year survival rate approaching 50%5. It has beensuggested that the use of a different surgical procedure mayexplain this difference in survival of patients with the samedisease stage. In Japan, standard guidelines have been esta-blished for lymph node dissection6: extended lymphadenec-tomy is routinely used, and five-year survival rates after ex-tended lymphadenectomy (D2) reported in retrospective stu-dies are significantly higher than those reported following alymphadenectomy limited to the perigastric lymph nodes(D1)7. D2 lymphadenectomy is used less widely in the West. Inan overview on gastric cancer treatment in the USA, D2 dis-sections were performed in only 4 to 7% of cases2, 8-9. Thescepticism expressed by Western surgeons may be justifiedin view of the doubts regarding the therapeutic value of ex-tended lymphadenectomy, strengthened by previous unfa-vourable results in Western countries9, and by the negativeimpact the procedure was found to have on survival in pre-vious randomized clinical trials10-11, although conducted onsmall series. Moreover, extended lymphadenectomy is diffi-cult to perform, requires a longer operating time and incurs ahigh incidence of mortality and morbidity. One randomizedclinical trial in England12 and another in Holland13, confir-med that there is a significant increase in the mortality andmorbidity rates after D2 lymphadenectomy with respect toD1 (in the English study, morbidity was 28% for D1 and 46%for D2 and the mortality rate was 6.5% for D1 and 13% forD2; in the Dutch study, mortality and morbidity were 25%and 4% respectively in the D1 group and 43% and 10% res-pectively in the D2 group). These differences were related tothe high percentage of patients who underwent splenectomyand/or distal pancreaectomy. In the English study there wasno evidence that D2 resection benefited overall survival: thefive-year survival rate in the D1 and D2 arms was 35% and33%, respectively. Similar negative survival outcomes follo-wing D2 lymphadenectomy were reported in the Dutch study:five-year survival rates were 45% for the D1 group and 47%for the D2 group and cumulative risks of relapse at five yearwere 43% and 37% for D1 and D2, respectively. However,after a median follow-up of 11 years, a significant survivalbenefit was observed for N2-positive patients of the D2group: 20% are still alive14. However, the results of these multicentric studies may becriticized for the following reasons:a) the standarization of lymph nodes dissection wasdoubtful15-16: in 51% of the patients who underwent D2 dis-section, no lymph nodes were obtained from two or morestations dissected, and in 36% of the D1 dissections the num-ber of nodes removed was smaller than that required;b) a large number of distal pancreatectomies and splenec-tomies were performed, but these procedures can be avoidedfor a adequate D2 lymphadenectomy;c) with a view to achieving a high rate of accrual, severalhospitals participated in the study, and therefore the mediannumber of patients operated on by each surgeon was verysmall: the morbidity and mortality of surgical procedures arerelated to the number of procedures performed by each sur-geon.The prognostic value of extended lymphadenectomy wasDepartment of Oncological and Surgical SciencesClinica Chirurgica 2University of PadovaItalyD2 or non D2-lymphadenectomy in gastric cancerD. Nitti MD, A. Marchet MD, M. Olivieri MD, A. Ambrosi PhD, R. Mencarelli MD, F. Farinati MD, C. Belluco MD, M. Lise MDCarcinoma de estómagoconfirmed in the 5th edition of the TNM (UICC 1997), inwhich the N classification was modified: it is now based onthe number of lymph nodes involved (N0, no lymph nodesmetastases; N1, 1 to 6 positive lymph nodes; N2, 7 to 15positive lymph nodes; and N3, more than 15 positive lymphnodes). Moreover, the UICC has stated that the “histologicalexamination of a regional lymphadenectomy specimen willordinarily include 15 or more lymph nodes”. It is thereforenecessary to remove at least 15 lymph nodes in order to beable to classify a patient as “N2 or N3”.The EORTC experienceIn 1989, the Gastrointestinal Tract Cancer CooperativeGroup (GITCCG) of the European Organization for Researchand Treatment of Cancer (EORTC) closed a phase III clinicaltrial on adjuvant chemotherapy with the FAM regimen. Ineight European Countries, 314 patients who had undergonecurative resection for stage II or stage III gastric carcinomawere randomized to receive the modified FAM regimen, orno further treatment. A retrospective analysis of this studywas made to evaluate the effect of prognostic factors on sur-vival and time to recurrence in relation to the characteristicsof patients and tumors, and treatment17. For each patient, anevaluation of regional lymphadenectomy was made on thebasis of partial or complete D1, D2 or D3 dissection in rela-tion to tumor site. After comparing surgical and pathologydata, lymphadenectomy was classified as “adequate” whenthe extent of lymph node dissection was wider than lymphnode metastatic diffusion, “partially adequate” when thesecoincided and “inadequate” when the dissection did not en-compass metastatic diffusion (random lymph node biopsies)or when there was a fault in the surgical technique (e.g., gre-ater omentum not removed).Since pathology data were incomplete in 5 out of 314 ca-ses, the series evaluated for quality of surgery consisted of309 patients. Resection was considered “adequate” in 102patients (33%), “partially adequate” in 131 (42.4%), and“inadequate” in 76 (24.6%). At univariate analysis, statisti-cally significant differences in survival and time to progres-sion emerged for T, N, disease-stage or adequacy of sur-gery. Survival was significantly better for patients who had“adequate” than in those who had “partially adequate” and“inadequate” surgery (p<0.001) and the differences in survi-val between “adequate” and “inadequate” or “partially ade-quate” surgery persisted when stage II and stage III patientswere analyzed separately.Multivariate analysis retained preoperative Hb level, T, N,and adequacy of surgery for duration of survival, and T, N,adequacy of surgery and adjuvant chemotherapy for time torecurrence. These data, show that inadequate lymphadenec-tomy may result not only in stage shifting, but also in com-promised radicality in patients with “curable” disease17. In the nineties the EORTC evaluated the efficacy of theOncología, 2004; 27 (4):162-16535Fig. 1. Overall survival according to lymph nodes status (Clinica Chirurgica II, Padova, Italy).FAMTX regimen versus surgery alone in a randomized clini-cal trial on patients with radically resected gastric cancer. Atthat time, the International Collaborative Cancer Group(ICCG) was also investigating 5-FU+Epirubicin (EPI)+ MTXwith Leucovorin rescue (FEMTX) versus surgery alone. Thetwo trials were considered similar enough by an IndependentData Monitoring Committee to be analyzed together. FromJuly 1990 to March 1998, 397 untreated patients were ran-domised in both trials. Two hundred and six patients from 23EORTC institutions (trial opened in February’91) and 191from 16 ICCG institutions were registered. At a preliminaryanalysis, the overall survivals in the EORTC trial appearedbetter than those in the ICCG trial18.An analysis of the surgical procedures used in the twotrials showed important differences between extent of sur-gery. In the EORTC trial 89% of patients underwent D2 dis-section. The median number of lymph nodes removed was13 in the ICCG study, whereas 74% of patients had 13 ormore nodes removed in the EORTC trial. Although a directcomparison cannot be made, it appears likely that the moreradical surgery performed in the EORTC study resulted in agreater survival benefit than the less radical surgery perfor-med in the ICCG trial18 .Personal experienceTo evaluate the impact of D2 lymphadenectomy on thesurvival of patients who undergo radical resection for gastriccancer and to demonstrate the role of the other prognosticfactors, recently we reviewed the data of 445 consecutive pa-tients operated on at Clinica Chirurgica II, Padova Univer-sity19-20. Between February 1980 and December 1999, among445 patients with histologically confirmed carcinoma of thestomach, 314 patients underwent radical resection (R0).Thirty-seven were excluded from the analysis: the study istherefore based on data from 277 patients who underwentradical resection (R0). D2 dissection was performed in 259(93.6%), and D1 lymphadenectomy in 18 (6.4%) cases.From 277 patients, a total of 7,668 lymph nodes (median27; mean, 27.6; range 11-62) were removed and exami-ned. Lymphadenectomy included more than 15 lymph nodeswas performed in 245 cases (88.4%): 11 to 25 nodes in 116patients (41.8%) and more than 25 nodes in 161 patients(58.2%). A total of 1,280 lymph nodes were metastatic (me-dian, 5; mean, 8.25; range, 1-47). For the 277 patients, the5-year survival rate was 57%; it was 82% for the 117 pa-tients without lymph node metastases, and 37% for the 160patients with lymph node metastases (Fig. 1). Table I reportsfindings at univariate analysis for prognostic factors. When multivariate analysis was performed, only age, T,and metastatic/examined lymphnodes ratio (N ratio) werefound to be independent prognostic factors (RR of N ratio1=1.60, RR of N ratio 2=1.72; RR of N ratio 3=5.52) (TableII).In our study, which considered almost exclusively D2lymphadenectomy, the overall survival rate appears betterthan that usually reported in western countries, and similar tothat reported in Japanese trials. These results could be rela-ted to the quality of surgery performed in our series. We the-refore believe that D2 lymphadenectomy allows accurate di-sease staging of the disease and can be “curative” in patientswith gastric cancer confined to the locoregional area.References1. Hundahl SA, Phillips JL, Menck HR. The National Cancer DataBase Report on poor survival of US gastric carcinoma patientstreated with gastrectomy. Fifth Edition American Joint Commit-tee on Cancer Staging, proximal disease, and the “different di-sease” hypothesis. Cancer 2000; 88:921-32.2. Berrino F, Sant M, Verdecchia A, et al. Survival of cancer pa-tients in Europe. The Eurocare study. IARC Sci, 1995; Publ.No.132.D. Nitti y cols.36TABLE IUnivariate analysis according to clinico-pathological factorsin 277 patients who underwent radical resection for gastriccancer (Clinica Chirurgica II, Padova, Italy)Factor p-valueSex 0.299Age 0.048Site <0.001Surgery 0.002Splenectomy <0.0001Grading <0.001Lymphatic invasion <0.001Venous invasion <0.001Ming 0.608Lauren 0.802T <0.001Anatomical location of metastatic nodes (n) <0.001Number of metastatic nodes (N) <0.001Metastatic/examined nodes ratio <0.0001TABLE IIMultivariate analysis according to clinico-pathologicalfactors in 277 patients who underwent radical resectionfor gastric cancer (Clinica Chirurgica II, Padova)Factor p R.R. 95% C.I.Age 0.01 1.57 1.09-2.27T 0.000T1b 0.35 1.44 0.66-3.14T2a 0.39 1.41 0.63-3.14T2b 0.001 3.18 1.56-6.48T3 0.02 2.55 1.14-5.68T4 0.000 8.18 2.69-24.90N ratio 0.000N ratio 1 0.10 1.60 0.90-2.86N ratio 2 0.06 1.72 0.95-3.10N ratio 3 0.000 5.52 3.15-8.63Oncología, 2004; 27 (4):162-165373. Siewert JR, Bottcher K, Roder JC, Busch R, Hermanek P, MeyerHJ. Prognostic relevance of lymph node dissection in gastriccarcinoma. German Gastric Carcinoma Study Group. Br J Surg1993; 80:1015-8.4. Gunderson LL. Gastric cancer. Patterns of relapse after surgi-cal resection. Seminars in Radiation Oncology 2002;12:150-61.5. Harrison LE, Karpeh MS, Brennan F. Extended lymphadenec-tomy is associated with a survival benefit for node-negativegastric cancer. J Gastrointest Surg 1998; 2:126-31.6. Noguchi Y, Imada T, Matsumoto A, Coit DG, Brennan MF. Ra-dical surgery for gastric cancer: a review of the Japanese expe-rience. Cancer 1989; 64:2053-62.7. Maruyama K, Gunven P, Okabayashi K, Sasako M, KinoshitaT. Lymph nodes metastases in gastric cancer. Ann Surg 1989;210:596-602. 8. Hundal SA, Macdonald JS, Benedetti J, Fitzsimmons T, for theSouthwest Oncology Group and the Gastric Intergroup. Surgi-cal treatment variation in a prospective, randomized trial ofchemoradiotherapy in gastric cancer: the effect of undertreat-ment. Ann Surg Oncol 2002; 9:278-86.9. Wanebo HJ, Kennedy BJ, Winchester DP, Fregmen A, StewartAK. Gastric carcinoma: does lymph node dissection alter thesurvival? J Am Coll Surg 1996; 183:616-24.10. Dent DM, Madden MV, Price SK. Randomized comparison ofR1 and R2 gastrectomy for gastric carcinoma. Br J Surg 1988;75:110-2.11. Diggory RT, Cuschieri A. R2/R3 gastrectomy for carcinoma: anaudited experience of a consecutive series. Br J Surg 1985;72:146-8.12. Cuschieri A, Weeden S, Fielding J, et al. Patient survival afterD1 and D2 resections for gastric cancer. Long term results ofthe MRC randomised surgical trial. Br J Cancer 1999;79:1522-30.13. Bonekamp JJ, Hermans J, Sasako M, van de Velde CJH. Exten-ded lymph-node dissection for gastric cancer. N Engl J Med1999; 340:908-14.14. Peeters K., van de Velde CHJ. Improving treatment outcome forgastric cancer: the role of surgery and adjuvant therapy. J ClinOncol 2003; 21(23s):272s-3s.15. Brennan MF. Lymph node dissection for gastric cancer. NewEngl J Med 1999; 340:956-8.16. Sasako M. Risk factors for surgical treatment in the Dutch Gas-tric Cancer Trial. Br J Surg1997; 84:1567-71.17. Lise M, Nitti D, Marchet A, Sahmoud T, Duez N, et al. Prognos-tic factors in resectable gastric cancer: results of EORTC studyN°40813 on FAM adjuvant chemotherapy. Ann Surg Oncol1995; 2:495-501.18. J. Wils, D. Nitti, J. Guimaraes–Dos-Santos, G. Fountzilas, F.Conte, C. Sava, A. Tres, E. Sanchez, J. Homewood, M.L. Couv-reur, E. Hall, B. Baron, M. Lise. Randomized phase III studies ofadjuvant chemotherapy with FAMTX or FEMTX in resected gas-tric cancer. Pooled results of studies from the EORTC GI-groupand the ICCG. Proceedings of ASCO 2002. Abstract 521.19. Nitti D, Marchet A, Belluco C, Olivieri M, Ambrosi A, Mamma-no E, Lise M. Ratio between metastatic and examined lymphnodes is an independent prognostic factor after D2 resection forgastric cancer: analysis of a large European monoinstitutionalexperience. Ann Surg Oncol 2003; 10:1077-85.20. Nitti D, Marchet A, Olivieri M, Ambrosi A, Mencarelli R, FarinatiF, Belluco C, Lise M. Limphadenectomy in patients with gastriccancer: a critical review. Tumori 2003; 2:S35-S38.Correspondence:Prof. Donato Nitti Istituto di Clinica Chirurgica Generale IIUniversità di PadovaVia Giustiniani, 235128 - Padova, ItalyE-mail: donato.nitti@unipd.it

D2 or non D2-lymphadenectomy in gastric cancer

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D2 or non D2-lymphadenectomy in gastric cancer

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