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Survival results of a multicentre phase II study to evaluate D2 gastrectomy for gastric cancer

Survival results of a multicentre phase II study to evaluate D2 gastrectomy for gastric cancer British Journal of Cancer (2004) 90, 1727 – 1732 & 2004 Cancer Research UK All rights reserved 0007 – 0920/04 $25.00 www.bjcancer.com Survival results of a multicentre phase II study to evaluate D2 gastrectomy for gastric cancer ,1 2 3 1 4 M Degiuli , M Sasako , A Ponti and F Calvo for the Italian Gastric Cancer Study Group (IGCSG) 1 2 3 Department of Oncology, Division of Surgery, Via Cavour, 31, 10123 Turin, Italy; National Cancer Center Hospital, Tokyo, Japan; CPO Piemonte, ASL 1, Turin, Italy; IGCSG include the following: Tiziano Allone, Dario Andreone, Alessandro Balcet, Riccardo Bussone, Marco Calgaro, Fabio Calvo, Lorenzo Capussotti, Maurizio Degiuli, Gianruggero Fronda, Marcello Garavoglia, Mauro Garino, Luigi Locatelli, Paolo Mello Teggia, Mario Morino, Fabrizio Olivieri, Fabrizio Rebecchi, Donatella Scaglione and Tito Soldati. Curative resection is the treatment of choice for potentially curable gastric cancer. Two major Western studies in the 1990s failed to show a benefit from D2 dissection. They showed extremely high postoperative mortality after D2 dissection, and were criticised for the potential inadequacy of the pretrial training in the new technique of D2 dissection, prior to the phase III studies being initiated. The inclusion of pancreatectomy and splenectomy in D2 dissection was associated with increased morbidity and mortality. Following these results, we started a phase II trial to evaluate the safety and efficacy of pancreas-preserving D2 dissection. The results of this trial regarding the safety of pancreas preserving D2 dissection were published in 1998. In this paper, we present the survival results of this phase II trial to confirm the rationale of carrying out a phase III study comparing D1 vs D2 dissection for curable gastric cancer. Italian patients with histologically proven gastric adenocarcinoma were registered in the Italian Gastric Cancer Study Group Multicenter trial. The study was carried out based on the General Rules of the Japanese Research Society for Gastric Cancer. A strict quality control system was achieved by a supervising surgeon of the reference centre who had stayed at the National Cancer Center Hospital, Tokyo, to learn the standard D2 gastrectomy and the postoperative management. The standard procedure entailed removal of the first and second tier lymph nodes. During total gastrectomy, the pancreas was preserved according to the Maruyama technique. Complete follow-up was available to death or 5 years in 100% of patients and the median follow-up time was 4.38 years. Out of 297 consecutive patients registered, 191 patients were enrolled in the study between May 1994 and December 1996. The overall morbidity rate was 20.9%. The postoperative in-hospital mortality was 3.1%. The overall 5-year survival rate among all eligible patients was 55%. Survival was strictly related to stage, depth of wall invasion, lymph node involvement and type of gastrectomy (distal vs total). Our results suggest a survival benefit for pancreas-preserving D2 dissection in Italian patients with gastric cancer if performed in experienced centres. A phase III trial among exclusively experienced centres is urgently needed. British Journal of Cancer (2004) 90, 1727–1732. doi:10.1038/sj.bjc.6601761 www.bjcancer.com Published online 6 April 2004 & 2004 Cancer Research UK Keywords: gastrectomy; lymph node dissection; survival; D2 gastrectomy Gastric cancer, which is the commonest cancer in Japan, remains a Favourable patient survival after D2 gastrectomy has also been major cause of death also in Western countries. In Italy, it reported by some other non-Japanese retrospective nonrando- represents the third most frequent cause of death from cancer in mised trials (Pacelli et al, 1993; Siewert et al, 1993). both male and female patients (Decarli et al, 1998). Data from Nevertheless, the two large prospective randomised trials Italian Cancer Registries show a 27% 5-year survival rate (Rosso recently performed in the West (the MRC and the Dutch et al, 2001). This is consistent with other survival rates reported in randomised surgical trials) failed to demonstrate a survival benefit Western countries. On the contrary, large retrospective Japanese for D2 gastrectomy as compared to D1 resection (Bonenkamp et al, series have shown significantly higher 5-year survival rates after 1999; Cuschieri et al, 1999). Furthermore, these trials showed a radical gastrectomy. This impressive difference is largely related to significant increase in post-operative morbidity and mortality after earlier diagnosis, but it is possible that the more extensive lymph extended dissection. node dissection performed in Japan, where the stomach is usually These unfavourable results have been attributed mainly to the en removed along with the first and second tier nodal stations (D2 bloc removal of the spleen and the tail of the pancreas for middle gastrectomy) (Sasako et al, 1997), also contributes. and upper third tumours in the D2 arms of both trials. Furthermore, the lack of experience in this technique of dissection and in postoperative care by each surgeon participating in these *Correspondence: Dr M Degiuli, E-mail: [email protected] trials has been claimed as one of the reasons for the results Received 13 October 2003; revised 3 February 2004; accepted 5 (Bonenkamp et al, 1995; Cuschieri et al, 1996). Both studies were February 2004; published online 6 April 2004 carried out without pretrial training and without preliminary Clinical Clinical Survival of IGCSG D2 gastrectomy phase II study M Degiuli et al studies to confirm the safety of the procedure locally, and were Before starting the trial, several meetings were organised among concluded before many surgeons would have reached the plateau participating centres to explain the terminology, to debate the of the learning curve. proper indications and demonstrate the surgical technique. At The Italian Gastric Cancer Study Group (IGCSG) was set up in least one of the two surgeons of each participating institution 1994 to confirm the safety and efficacy in survival of D2 resection observed the first 10 procedures in this trial, which were with pancreas preservation, and a strict quality control system was performed at the reference centre. Afterwards, MD attended the implemented in a prospective one-arm phase II study. In 1998, we first three operations performed at each institution. showed comparable postoperative morbidity and mortality rates with those reported after the standard resection, and documented Registration that the D2 resection with preservation of the pancreas could be offered as a safe radical treatment of gastric cancer for Western The study was organised and directed from a central office at the patients in experienced centres (Degiuli et al, 1998). reference centre (Department of Oncology, Division of Surgery, We now report the survival data of the patients of the same trial. Turin, Italy). Data on enrolment, surgical procedures, histopatho- logic findings, postoperative course and patient follow-up evalua- tion were collected by the surgeon at each institution and posted to PATIENTS AND METHODS the data centre at the central office. Patients were followed up at regular intervals: every 3 months during the first 2 years and every Eligibility and assessment of curability 6 months thereafter. In addition, an enquiry on vital status and cause of death was collected for all patients at the municipal roster Patients eligible for participation in this study were to have office. The final follow-up date was 31 December 2002. Complete histologically proven and preoperatively potentially curable follow-up was available in 100% of patients; the median follow-up adenocarcinoma of the stomach. Patients who required emergency time for those alive at the end of the study was 7.4 years. procedures, who harboured a coexisting cancer, who were 480 years old or who had a comorbid cardiorespiratory dysfunction that would preclude more extensive dissection were excluded. Statistical methods After preoperative staging to exclude clinical evidence of distant metastasis, all patients were registered and underwent staging Sample size calculations were performed assuming to achieve a 5- laparotomy. Eligible cases were those without any evidence of year overall survival of 50%, intermediate between Western and peritoneal and/or liver metastasis, involvement of the oesophagus, Japanese series. The required number for enrolment was then set cardias or duodenum, and biopsy-proven metastasis in para-aortic to about 200 patients, based on the desired level of power precision and/or retropancreatic nodes. in estimating this parameter (95% confidence interval: 42.9– 57.1%, power 80%). Confidence intervals are based on exact binomial probabilities. Overall survival was computed by the Treatment Kaplan–Meier method using the BMDP statistical package for all The surgical protocol was based on the general rules of the eligible subjects and for subpopulations grouped on the basis of Japanese Research Society for Gastric Cancer (JRSGC, 1981a, b). selected variables. Both deaths due to the disease and deaths The D2 dissection entailed removal of the first and second tier without evidence of recurrence were counted as events in the nodes along with the lymph nodes of the left side of the analysis of survival. The gastric cancer-specific survival curve was hepatoduodenal ligament. During total gastrectomy, the spleen also calculated, with deaths due to other causes being censored. was removed while the tail of the pancreas was preserved according to the technique described by Maruyama et al (1995), unless it was suspected to be invaded by the tumour. In the case of RESULTS a clinical T1 tumour, splenectomy was not carried out. In total, 297 patients with histologically proven adenocarcinoma of Distal gastrectomy was performed in cases of early gastric the stomach were registered from the nine institutions over 2 cancer (EGC) or well demarcated advanced gastric cancer (AGC), 2 years (May 1994 – December 1996). Of these, 106 patients were such as Borrman type 1 or 2, with a tumour-free margin of at least found ineligible for the study mostly because more advanced 2 cm, or in case of infiltrative AGC, type 3 or 4, with a tumour-free disease was identified at laparotomy, as outlined in the protocol. In margin of at least 5 cm to the proximal resection line. A total all, 191 patients fulfilled the criteria of eligibility and were entered gastrectomy was performed in all other cases. into the study. Table 1 briefly summarises the characteristics of the For all enrolled patients, chemotherapy was not given until eligible patients (median age: years), the procedures performed, recurrence was diagnosed. the pathologic stage of the disease and the early outcome. No patients were lost to follow-up. The median follow-up time of Pathological classification all patients alive at the end of the study was 7.4 years (range 6–8.7 years). All patients were followed up till death or for at least 6 As compared with our previous papers, tumours were restaged years. Of the 191 resected patients, 96 (50.3%) died. Six out of these according to the fifth edition of UICC TNM Classification of 96 patients died with early postoperative complications (3.1%). Malignant Tumours and the Japanese Classification of Gastric During the follow-up, 26 patients (13.6%) died without recurrence Carcinoma, 2nd English edition (UICC, 1997; JGCA, 1998). of gastric cancer. Death with recurrence of gastric cancer occurred in 70 patients (36.7%). Quality control A surgeon from the reference centre (MD) stayed at the National Decrease of postoperative in-hospital mortality Cancer Center Hospital, Tokyo, to learn the D2 dissection from a specialist Japanese surgeon (MS). He was given didactic videos, Postoperative in-hospital mortality may have decreased during the papers and explanatory booklets edited by Japanese authors. MD study period. It was 5.26% in 1994 (38 procedures performed), became the supervisor of the trial. 2.11% in 1995 (95 procedures) and 1.75% in 1996 (57 procedures). The IGCSG was set up in April 1994 and nine institutions Although suggestive of a decreasing trend, due to small numbers participated. Each centre had two surgeons attending all the percentages are not significantly different from each other 2 2 operations. (X ¼ 0.36 (df 2), P¼ 0.55; X slope¼ 0.94 (df 1), P¼ 0.33). British Journal of Cancer (2004) 90(9), 1727 – 1732 & 2004 Cancer Research UK Survival of IGCSG D2 gastrectomy phase II study M Degiuli et al Table 1 Patient characteristics 1.00 No. of patients (%) No. of patients (191¼ 100%) (%) (191¼ 100%) Sex M/F 114 (59.6)/77 (41.4) IIIB 25 (13.1) Age o50 years 31 (16.2) IV 23 (12.1) 0.80 Age 50 – 69 years 103 (53.9) Pathological stage Age 70+ years 57 (29.8) T1 68 (35.6) Location of tumour T2 58 (30.3) Distal third (A,AM) 116 (60.8) T3 58 (30.3) 0.60 Middle third 52 (27.2) T4 7 (3.8) (M,MC,CM) Upper third (C,CM)l 13 (6.8) Nodal status More than two-thirds 6 (3.1) N0 78 (35.4) of stomach 0.40 Stump 4 (2.1) N1 41 (21.5) Japanese stage N2 56 (29.3) grouping IA 53 (27.7 ) N3 (location 16 (8.4) no 12) 0.20 IB 22 (11.5) Type of gastrectomy II 31 (16.2) Distal 124 (64.9) IIIA 37 (19.4) Total 67 (35.1) 0.0 Overall survival 0123456789 10 For calculating the incidence of deaths due to the disease (n¼ 70), Figure 1 Overall 5-year survival among all eligible. patients (J) and the cause of death according to clinical records was used. In those among patients with deaths related to cancer only (C) (95% confidence few records where the cause was missing, the cause of death listed interval 47.9, 62.1). in the Piemonte Cancer Registry (from the municipal roster office) was used. The overall 5-year survival rate among all eligible patients was 55.0% (95% confidence interval 47.9, 62.1) (Figure 1). The gastric cancer specific survival rate was 65% after 5 years and 62.5% after 1.00 6 years (Figure 1). Survival by TNM stages The 5-year survival rate was significantly dependent upon the stage of the disease (Po0.001). It was 95, 87.5, 57.5, 42.5, 22.5 and 2.5% 0.80 in patients with TNM stage IA, IB, II, IIIA, IIIB and IV, respectively (Figure 2). To allow comparison of these results with other reports, the results using the previous TNM classification are also shown in Table 2. 0.60 Survival by depth of invasion Survival of patients was significantly influenced by depth of invasion (Po0.001). The 5-year survival rate was 90, 52.5, 25 and 12.5 for patients with T1, T2, T3 and T4, respectively (Figure 3). 0.40 Survival by nodal involvement We analysed patient survival according to the two nodal staging systems: the 1997 TNM and the 1998 JGCA classification. 0.20 The. 5-year survival rates of pN0, pN1, pN2 and pN3 by 1997 TNM were 85, 52.5, 32.5 and 2.5%, respectively. Those by the JGCA classification were 47.5%, 35 % and 0% for pN1, pN2 and pN3, respectively (Figure 4). 0.0 Survival by type of gastrectomy 0123456789 10 Patients who underwent distal gastrectomy showed a higher 5-year survival rate (70%) as compared with those who received total Figure 2 Survival after resection according to 1997 TNM stage (A is IA; resection (40%) (Po0.001). B is IB; C is II; D is IIIA; E is IIIB; F is IV). & 2004 Cancer Research UK British Journal of Cancer (2004) 90(9), 1727 – 1732 Clinical Clinical Survival of IGCSG D2 gastrectomy phase II study M Degiuli et al Table 2 Survival among all eligible patients and according to old TNM stage in the most recent series Author No of patients Type of gastrectomy (No. of patients) 5 years survival (%) IA IB II IIIA IIIB IV Wanebo et al (1993) 9057 D0 – 1 26 59 44 29 15 9 3 Siewert et al (1993) 1182 D1 (379) 86 72 26 25 27 28 D2 (803) 85 68 55 38 17 16 b b Pacelli et al (1993) 238 D2 65 96 73 63 40 33 0 Cuschieri et al (1999) 400 D1 (200) 35 69 22 11 Not included D2 (200) 33 58 31 11 b b Bonenkamp et al (1999) 711 D1 (380) 34 81 60 38 11 13 0 D2 (331) 81 61 42 28 13 28 D1 (380) 33 D2 (331) Sasako et al (1997) 2541 D2 – 4 66 92 90 76 59 36 7 IGCSG et al (2004) 191 D2 55 92.5 87.5 60 40 20 2.5 a b Only Ro resection. Only curative resection. 1.00 1.00 0.80 0.80 0.60 0.60 0.40 0.40 0.20 0.20 0.0 0.0 0123456789 10 0123456789 10 Figure 3 Survival by depth of invasion (pT) (A is T1; B is T2; C is T3; D is Figure 4 Survival by JGCA nodal involvement (A is N0;B is N1; C is N2; T4). D is N3). if the operation is performed in specialised centres with a strict DISCUSSION quality control system, and without removing the pancreas during The role of the extended lymph node dissection in improving long- total gastrectomy unless it is suspected to be involved by the term survival after gastrectomy for gastric cancer is still not proven tumour (Degiuli et al, 1998). by RCTs. Moreover, the Dutch and British trials have shown The present study has also shown good survival data. The increased morbidity and mortality figures after D2 gastrectomy overall 5-year survival rate was 55%. Moreover, the disease-specific (Bonenkamp et al, 1995; Cuschieri et al, 1996). Potential reasons 5-year survival was 65%. Our results are almost equivalent to those for this unfavourable outcome include the lack of surgical reported by Sasako after 2541 extended gastrectomies performed at skilfulness/training and poor quality control, and the routine the National Cancer Center Hospital, Tokyo, during the period removal of the spleen and tail of the pancreas in total gastrectomy ‘1982–1991’ (66%) (Sasako et al, 1997, pp 223–248). Not only the (Cuschieri et al, 1996). overall survival rate but also the stage-specific survival rates after In our previous paper, we showed that it is possible to achieve D2 dissection were much better in this study than those of the D2 low morbidity and mortality after extended lymph node dissection, arm of the Dutch and MRC trials (Table 2). British Journal of Cancer (2004) 90(9), 1727 – 1732 & 2004 Cancer Research UK Survival of IGCSG D2 gastrectomy phase II study M Degiuli et al The discrepancy between our data and data from other Western Table 3 Relative experience of participating centres in Italian, British and series could be explained by differences in the patient population Dutch trials. or by differences in surgical technique. a b IGCSG DGCG MRC Regarding the patient populations, the eligibility criteria from the two large prospective randomised series are totally comparable No. of centres 9 80 322 to those adopted in our trial. No. of surgeons 9 pairs 11/85 32 With respect to the clinical and pathological stages, no major Duration of enrolment (years) 2.5 4 7 differences appear in the reported series apart from a clear No of patients 191 331 200 prevalence of early gastric cancer in the Japanese series. The Average no. of procedures/hospital/year 7 1.5 1 prevalence of early tumours (stage I disease) is close to 50% in the a b Dutch Gastric Cancer Group trial. Medical Research Council, British Trial. Japanese series, while it is 35.6% in our population, 36% in the Supervising/local surgeons. MRC series, 26% in the Dutch trial and 19.6% in an American patient care study (16). Siewert gives the figures for IA and IB stages, which are, respectively, 13.8 and 13.4% (3). In the present series, the number of patients with TNM stage less than III is substantial (106 patients, 55.4%) and might be partly responsible Table 4 Spleen and pancreas removal during total gastrectomies in for our good survival data. Italian, British and Dutch trials To avoid the confounding effect of stage migration, we should compare the results of series reporting D2 a b IGCSG no. (%) DGCG no. (%) MRC no. (%) dissection with each other. Our results are similar to those previously reported by Pacelli et al. (1993) in their retrospective Total gastrectomies 67 (100) 126 (100) 108 (100) trial and by Siewert et al (1993) in their prospective nonrando- Splenectomies 49 (73.1) 124 (98.4) 131 (121.2) mised trial. Pancreatectomies 10 (14.9) 98 (77.7) 113 (104.6) The main criticism that has been directed towards the a b c Medical Research Council, British trial. Dutch Gastric Cancer Group trial. A total of recent prospective randomised European trials has been 25 splenectomies performed during a distal gastrectomy. Five pancreatectomies the lack of experience of the surgeons participating in the performed during a distal gastrectomy. study. The contrast in postoperative mortality between the Dutch or British trials and our own study clearly demonstrated the danger of carrying out this procedure, let alone an RCT, without sufficient pretrial training. Clearly a one-arm study, equivalent to As already indicated, subset analysis of the Dutch the phase II study in medical treatment, is an appropriate and MRC trials documented that the higher morbidity in the D2 preliminary to a phase III trial of complex and potentially arm is mostly due to pancreas and spleen removal (Cuschieri et al, hazardous surgery. MS, who was supervisor of both the Dutch 1996). Hence, pancreas preservation was adopted as standard and the Italian study, believes that the Dutch study was flawed by procedure in D2 dissection in the present trial. Therefore, the early randomisation of patients, and the inclusion of many small- pancreas was removed only when it was suspected to be involved volume hospitals. It is suggested that a new surgical technique by the tumour (T4). Furthermore, during total gastrectomy, requiring not only surgical skills but also good experience in splenectomy was not carried out in patients with clinical T1 postoperative care should only be tested in an RCT after tumour (Table 4). completion of sufficient training to carry it out safely. In fact, After confirming the low mortality and acceptable morbidity of the reported perioperative mortalities in these two major RCTs on pancreas-preserving D2 dissection, we started a phase III trail, D2 dissection were over 10%. Pancreaticoduodenectomy for comparing D1 vs D2 in 1998. The survival results shown in this pancreatic cancer or radical oesophagectomy for oesophageal paper suggest the benefits of D2 dissection, although a statistically cancer are more surgically aggressive procedures than D2 significant survival advantage needs to be confirmed through this gastrectomy and are recommended to be performed exclusively new randomised phase III trial. The aim of this phase III trial is to in specialised centres. They do not carry a risk of hospital document an increase of survival in the D2 arm with acceptable mortality of over 10% in such centres (Altorki and Skinner, 1997; increase of morbidity and without increase of mortality. Gordon et al, 1998; Bottger and Junginger, 1999; Lerut et al, 1999; Tsiotos et al, 1999; Gouma et al, 2000; Karl et al, 2000). Postoperative mortality of over 10% is no longer acceptable in any kind of cancer surgery. ACKNOWLEDGEMENTS Our own experience correlates well with the data given by Parikh et al (1996) about the duration of the learning We acknowledge the contribution of Tiziano Allone, MD, for his curve for D2 dissection, which should be more than 15 procedures. assistance with the data collection and performing the statistics; we Each participating centre treated 15 to more than 25 patients also thank Alessandra Spitale, Franca Gilardi and the Registro (seven procedures per year on an average) (Table 3), and Tumori Piemonte for conducting the follow-up of the study cohort. in every centre each patient was always treated by the same This research is supported by the Comprehensive 10-year Strategy two surgeons. Therefore, each centre and each surgeon should for Cancer Control of the Ministry of Health, Labour and Welfare have reached an optimal experience level, acquiring sufficient of Japan. technical skills regarding intra- and postoperative care during this We also thank the following surgeons who took part in the trial trial. Our results support the argument for training the surgeons participating in data collection and clinical evaluation: Dario prior to the initiation of a clinical trial although, at a practical level, Andreone (Orbassano), Alessandro Balcet (Torino), Riccardo a study target of 700–1000 patients would be very difficult to Bussone (Torino), Lorenzo Capussotti (Torino), Gianruggero conduct, and it might take more than 10 years to recruit all the Fronda (Torino), Marcello Garavoglia (Novara), Mauro Garino patients. (Torino), Luigi Locatelli (Torino), Paolo Mello Teggia (Orbassa- We observed an overall postoperative in-hospital mortality of no), Mario Morino (Torino), Fabrizio Olivieri (Novara), 3.1%: this rate has been decreasing from 5.2% in 1994, to 2.11% in Fabrizio Rebecchi (Torino), Donatella Scaglione(Torino) and Tito 1995 and finally to 1.7% in 1996. While not statistically significant, Soldati (Biella). We thank Bruce Mann for assistance with the this trend supports the concept of a learning curve. manuscript. & 2004 Cancer Research UK British Journal of Cancer (2004) 90(9), 1727 – 1732 Clinical Clinical Survival of IGCSG D2 gastrectomy phase II study M Degiuli et al REFERENCES Altorki NK, Skinner DB (1997) Occult cervical nodal metastasis in Japanese Research Society of Gastric Cancer (1981a) The general rules for esophageal cancer: preliminary results of three-field lymphadenectomy. the gastric cancer study in surgery and pathology. Part I. 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World J Surg 23: 913–919 Gouma DJ, van Geenen RC, van Gulik TM, de Haan RJ, de Wit LT, Busch UICC-International Union against Cancer (1997) TNM Classification of OR, Obertop H (2000) Rates of complications and death after Malignant Tumours, Sobin LH, Wittekinf CH (eds). New York: Wiley- pancreaticoduodenectomy: risk factors and the impact of hospital Liss Inc volume. Ann Surg 232: 786–795 Wanebo HJ, Kennedy BJ, Chmiel J, Steele Gjr, Winchester D, Osteen R Japanese Gastric Cancer Association (1998) Japanese classification of (1993) Cancer of the stomach. A patient care study by the American gastric carcinoma – 2nd English Edition. Gastric Cancer 1: 10–24 College of Surgeons. Am J Surg 218: 583–592 British Journal of Cancer (2004) 90(9), 1727 – 1732 & 2004 Cancer Research UK http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png British Journal of Cancer Springer Journals

Survival results of a multicentre phase II study to evaluate D2 gastrectomy for gastric cancer

Degiuli, M; Sasako, M; Ponti, A; Calvo, F
British Journal of Cancer , Volume 90 (9) – Apr 6, 2004
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Springer Journals
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Copyright © 2004 by The Author(s)
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Biomedicine; Biomedicine, general; Cancer Research; Epidemiology; Molecular Medicine; Oncology; Drug Resistance
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0007-0920
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10.1038/sj.bjc.6601761
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Abstract

British Journal of Cancer (2004) 90, 1727 – 1732 & 2004 Cancer Research UK All rights reserved 0007 – 0920/04 $25.00 www.bjcancer.com Survival results of a multicentre phase II study to evaluate D2 gastrectomy for gastric cancer ,1 2 3 1 4 M Degiuli , M Sasako , A Ponti and F Calvo for the Italian Gastric Cancer Study Group (IGCSG) 1 2 3 Department of Oncology, Division of Surgery, Via Cavour, 31, 10123 Turin, Italy; National Cancer Center Hospital, Tokyo, Japan; CPO Piemonte, ASL 1, Turin, Italy; IGCSG include the following: Tiziano Allone, Dario Andreone, Alessandro Balcet, Riccardo Bussone, Marco Calgaro, Fabio Calvo, Lorenzo Capussotti, Maurizio Degiuli, Gianruggero Fronda, Marcello Garavoglia, Mauro Garino, Luigi Locatelli, Paolo Mello Teggia, Mario Morino, Fabrizio Olivieri, Fabrizio Rebecchi, Donatella Scaglione and Tito Soldati. Curative resection is the treatment of choice for potentially curable gastric cancer. Two major Western studies in the 1990s failed to show a benefit from D2 dissection. They showed extremely high postoperative mortality after D2 dissection, and were criticised for the potential inadequacy of the pretrial training in the new technique of D2 dissection, prior to the phase III studies being initiated. The inclusion of pancreatectomy and splenectomy in D2 dissection was associated with increased morbidity and mortality. Following these results, we started a phase II trial to evaluate the safety and efficacy of pancreas-preserving D2 dissection. The results of this trial regarding the safety of pancreas preserving D2 dissection were published in 1998. In this paper, we present the survival results of this phase II trial to confirm the rationale of carrying out a phase III study comparing D1 vs D2 dissection for curable gastric cancer. Italian patients with histologically proven gastric adenocarcinoma were registered in the Italian Gastric Cancer Study Group Multicenter trial. The study was carried out based on the General Rules of the Japanese Research Society for Gastric Cancer. A strict quality control system was achieved by a supervising surgeon of the reference centre who had stayed at the National Cancer Center Hospital, Tokyo, to learn the standard D2 gastrectomy and the postoperative management. The standard procedure entailed removal of the first and second tier lymph nodes. During total gastrectomy, the pancreas was preserved according to the Maruyama technique. Complete follow-up was available to death or 5 years in 100% of patients and the median follow-up time was 4.38 years. Out of 297 consecutive patients registered, 191 patients were enrolled in the study between May 1994 and December 1996. The overall morbidity rate was 20.9%. The postoperative in-hospital mortality was 3.1%. The overall 5-year survival rate among all eligible patients was 55%. Survival was strictly related to stage, depth of wall invasion, lymph node involvement and type of gastrectomy (distal vs total). Our results suggest a survival benefit for pancreas-preserving D2 dissection in Italian patients with gastric cancer if performed in experienced centres. A phase III trial among exclusively experienced centres is urgently needed. British Journal of Cancer (2004) 90, 1727–1732. doi:10.1038/sj.bjc.6601761 www.bjcancer.com Published online 6 April 2004 & 2004 Cancer Research UK Keywords: gastrectomy; lymph node dissection; survival; D2 gastrectomy Gastric cancer, which is the commonest cancer in Japan, remains a Favourable patient survival after D2 gastrectomy has also been major cause of death also in Western countries. In Italy, it reported by some other non-Japanese retrospective nonrando- represents the third most frequent cause of death from cancer in mised trials (Pacelli et al, 1993; Siewert et al, 1993). both male and female patients (Decarli et al, 1998). Data from Nevertheless, the two large prospective randomised trials Italian Cancer Registries show a 27% 5-year survival rate (Rosso recently performed in the West (the MRC and the Dutch et al, 2001). This is consistent with other survival rates reported in randomised surgical trials) failed to demonstrate a survival benefit Western countries. On the contrary, large retrospective Japanese for D2 gastrectomy as compared to D1 resection (Bonenkamp et al, series have shown significantly higher 5-year survival rates after 1999; Cuschieri et al, 1999). Furthermore, these trials showed a radical gastrectomy. This impressive difference is largely related to significant increase in post-operative morbidity and mortality after earlier diagnosis, but it is possible that the more extensive lymph extended dissection. node dissection performed in Japan, where the stomach is usually These unfavourable results have been attributed mainly to the en removed along with the first and second tier nodal stations (D2 bloc removal of the spleen and the tail of the pancreas for middle gastrectomy) (Sasako et al, 1997), also contributes. and upper third tumours in the D2 arms of both trials. Furthermore, the lack of experience in this technique of dissection and in postoperative care by each surgeon participating in these *Correspondence: Dr M Degiuli, E-mail: [email protected] trials has been claimed as one of the reasons for the results Received 13 October 2003; revised 3 February 2004; accepted 5 (Bonenkamp et al, 1995; Cuschieri et al, 1996). Both studies were February 2004; published online 6 April 2004 carried out without pretrial training and without preliminary Clinical Clinical Survival of IGCSG D2 gastrectomy phase II study M Degiuli et al studies to confirm the safety of the procedure locally, and were Before starting the trial, several meetings were organised among concluded before many surgeons would have reached the plateau participating centres to explain the terminology, to debate the of the learning curve. proper indications and demonstrate the surgical technique. At The Italian Gastric Cancer Study Group (IGCSG) was set up in least one of the two surgeons of each participating institution 1994 to confirm the safety and efficacy in survival of D2 resection observed the first 10 procedures in this trial, which were with pancreas preservation, and a strict quality control system was performed at the reference centre. Afterwards, MD attended the implemented in a prospective one-arm phase II study. In 1998, we first three operations performed at each institution. showed comparable postoperative morbidity and mortality rates with those reported after the standard resection, and documented Registration that the D2 resection with preservation of the pancreas could be offered as a safe radical treatment of gastric cancer for Western The study was organised and directed from a central office at the patients in experienced centres (Degiuli et al, 1998). reference centre (Department of Oncology, Division of Surgery, We now report the survival data of the patients of the same trial. Turin, Italy). Data on enrolment, surgical procedures, histopatho- logic findings, postoperative course and patient follow-up evalua- tion were collected by the surgeon at each institution and posted to PATIENTS AND METHODS the data centre at the central office. Patients were followed up at regular intervals: every 3 months during the first 2 years and every Eligibility and assessment of curability 6 months thereafter. In addition, an enquiry on vital status and cause of death was collected for all patients at the municipal roster Patients eligible for participation in this study were to have office. The final follow-up date was 31 December 2002. Complete histologically proven and preoperatively potentially curable follow-up was available in 100% of patients; the median follow-up adenocarcinoma of the stomach. Patients who required emergency time for those alive at the end of the study was 7.4 years. procedures, who harboured a coexisting cancer, who were 480 years old or who had a comorbid cardiorespiratory dysfunction that would preclude more extensive dissection were excluded. Statistical methods After preoperative staging to exclude clinical evidence of distant metastasis, all patients were registered and underwent staging Sample size calculations were performed assuming to achieve a 5- laparotomy. Eligible cases were those without any evidence of year overall survival of 50%, intermediate between Western and peritoneal and/or liver metastasis, involvement of the oesophagus, Japanese series. The required number for enrolment was then set cardias or duodenum, and biopsy-proven metastasis in para-aortic to about 200 patients, based on the desired level of power precision and/or retropancreatic nodes. in estimating this parameter (95% confidence interval: 42.9– 57.1%, power 80%). Confidence intervals are based on exact binomial probabilities. Overall survival was computed by the Treatment Kaplan–Meier method using the BMDP statistical package for all The surgical protocol was based on the general rules of the eligible subjects and for subpopulations grouped on the basis of Japanese Research Society for Gastric Cancer (JRSGC, 1981a, b). selected variables. Both deaths due to the disease and deaths The D2 dissection entailed removal of the first and second tier without evidence of recurrence were counted as events in the nodes along with the lymph nodes of the left side of the analysis of survival. The gastric cancer-specific survival curve was hepatoduodenal ligament. During total gastrectomy, the spleen also calculated, with deaths due to other causes being censored. was removed while the tail of the pancreas was preserved according to the technique described by Maruyama et al (1995), unless it was suspected to be invaded by the tumour. In the case of RESULTS a clinical T1 tumour, splenectomy was not carried out. In total, 297 patients with histologically proven adenocarcinoma of Distal gastrectomy was performed in cases of early gastric the stomach were registered from the nine institutions over 2 cancer (EGC) or well demarcated advanced gastric cancer (AGC), 2 years (May 1994 – December 1996). Of these, 106 patients were such as Borrman type 1 or 2, with a tumour-free margin of at least found ineligible for the study mostly because more advanced 2 cm, or in case of infiltrative AGC, type 3 or 4, with a tumour-free disease was identified at laparotomy, as outlined in the protocol. In margin of at least 5 cm to the proximal resection line. A total all, 191 patients fulfilled the criteria of eligibility and were entered gastrectomy was performed in all other cases. into the study. Table 1 briefly summarises the characteristics of the For all enrolled patients, chemotherapy was not given until eligible patients (median age: years), the procedures performed, recurrence was diagnosed. the pathologic stage of the disease and the early outcome. No patients were lost to follow-up. The median follow-up time of Pathological classification all patients alive at the end of the study was 7.4 years (range 6–8.7 years). All patients were followed up till death or for at least 6 As compared with our previous papers, tumours were restaged years. Of the 191 resected patients, 96 (50.3%) died. Six out of these according to the fifth edition of UICC TNM Classification of 96 patients died with early postoperative complications (3.1%). Malignant Tumours and the Japanese Classification of Gastric During the follow-up, 26 patients (13.6%) died without recurrence Carcinoma, 2nd English edition (UICC, 1997; JGCA, 1998). of gastric cancer. Death with recurrence of gastric cancer occurred in 70 patients (36.7%). Quality control A surgeon from the reference centre (MD) stayed at the National Decrease of postoperative in-hospital mortality Cancer Center Hospital, Tokyo, to learn the D2 dissection from a specialist Japanese surgeon (MS). He was given didactic videos, Postoperative in-hospital mortality may have decreased during the papers and explanatory booklets edited by Japanese authors. MD study period. It was 5.26% in 1994 (38 procedures performed), became the supervisor of the trial. 2.11% in 1995 (95 procedures) and 1.75% in 1996 (57 procedures). The IGCSG was set up in April 1994 and nine institutions Although suggestive of a decreasing trend, due to small numbers participated. Each centre had two surgeons attending all the percentages are not significantly different from each other 2 2 operations. (X ¼ 0.36 (df 2), P¼ 0.55; X slope¼ 0.94 (df 1), P¼ 0.33). British Journal of Cancer (2004) 90(9), 1727 – 1732 & 2004 Cancer Research UK Survival of IGCSG D2 gastrectomy phase II study M Degiuli et al Table 1 Patient characteristics 1.00 No. of patients (%) No. of patients (191¼ 100%) (%) (191¼ 100%) Sex M/F 114 (59.6)/77 (41.4) IIIB 25 (13.1) Age o50 years 31 (16.2) IV 23 (12.1) 0.80 Age 50 – 69 years 103 (53.9) Pathological stage Age 70+ years 57 (29.8) T1 68 (35.6) Location of tumour T2 58 (30.3) Distal third (A,AM) 116 (60.8) T3 58 (30.3) 0.60 Middle third 52 (27.2) T4 7 (3.8) (M,MC,CM) Upper third (C,CM)l 13 (6.8) Nodal status More than two-thirds 6 (3.1) N0 78 (35.4) of stomach 0.40 Stump 4 (2.1) N1 41 (21.5) Japanese stage N2 56 (29.3) grouping IA 53 (27.7 ) N3 (location 16 (8.4) no 12) 0.20 IB 22 (11.5) Type of gastrectomy II 31 (16.2) Distal 124 (64.9) IIIA 37 (19.4) Total 67 (35.1) 0.0 Overall survival 0123456789 10 For calculating the incidence of deaths due to the disease (n¼ 70), Figure 1 Overall 5-year survival among all eligible. patients (J) and the cause of death according to clinical records was used. In those among patients with deaths related to cancer only (C) (95% confidence few records where the cause was missing, the cause of death listed interval 47.9, 62.1). in the Piemonte Cancer Registry (from the municipal roster office) was used. The overall 5-year survival rate among all eligible patients was 55.0% (95% confidence interval 47.9, 62.1) (Figure 1). The gastric cancer specific survival rate was 65% after 5 years and 62.5% after 1.00 6 years (Figure 1). Survival by TNM stages The 5-year survival rate was significantly dependent upon the stage of the disease (Po0.001). It was 95, 87.5, 57.5, 42.5, 22.5 and 2.5% 0.80 in patients with TNM stage IA, IB, II, IIIA, IIIB and IV, respectively (Figure 2). To allow comparison of these results with other reports, the results using the previous TNM classification are also shown in Table 2. 0.60 Survival by depth of invasion Survival of patients was significantly influenced by depth of invasion (Po0.001). The 5-year survival rate was 90, 52.5, 25 and 12.5 for patients with T1, T2, T3 and T4, respectively (Figure 3). 0.40 Survival by nodal involvement We analysed patient survival according to the two nodal staging systems: the 1997 TNM and the 1998 JGCA classification. 0.20 The. 5-year survival rates of pN0, pN1, pN2 and pN3 by 1997 TNM were 85, 52.5, 32.5 and 2.5%, respectively. Those by the JGCA classification were 47.5%, 35 % and 0% for pN1, pN2 and pN3, respectively (Figure 4). 0.0 Survival by type of gastrectomy 0123456789 10 Patients who underwent distal gastrectomy showed a higher 5-year survival rate (70%) as compared with those who received total Figure 2 Survival after resection according to 1997 TNM stage (A is IA; resection (40%) (Po0.001). B is IB; C is II; D is IIIA; E is IIIB; F is IV). & 2004 Cancer Research UK British Journal of Cancer (2004) 90(9), 1727 – 1732 Clinical Clinical Survival of IGCSG D2 gastrectomy phase II study M Degiuli et al Table 2 Survival among all eligible patients and according to old TNM stage in the most recent series Author No of patients Type of gastrectomy (No. of patients) 5 years survival (%) IA IB II IIIA IIIB IV Wanebo et al (1993) 9057 D0 – 1 26 59 44 29 15 9 3 Siewert et al (1993) 1182 D1 (379) 86 72 26 25 27 28 D2 (803) 85 68 55 38 17 16 b b Pacelli et al (1993) 238 D2 65 96 73 63 40 33 0 Cuschieri et al (1999) 400 D1 (200) 35 69 22 11 Not included D2 (200) 33 58 31 11 b b Bonenkamp et al (1999) 711 D1 (380) 34 81 60 38 11 13 0 D2 (331) 81 61 42 28 13 28 D1 (380) 33 D2 (331) Sasako et al (1997) 2541 D2 – 4 66 92 90 76 59 36 7 IGCSG et al (2004) 191 D2 55 92.5 87.5 60 40 20 2.5 a b Only Ro resection. Only curative resection. 1.00 1.00 0.80 0.80 0.60 0.60 0.40 0.40 0.20 0.20 0.0 0.0 0123456789 10 0123456789 10 Figure 3 Survival by depth of invasion (pT) (A is T1; B is T2; C is T3; D is Figure 4 Survival by JGCA nodal involvement (A is N0;B is N1; C is N2; T4). D is N3). if the operation is performed in specialised centres with a strict DISCUSSION quality control system, and without removing the pancreas during The role of the extended lymph node dissection in improving long- total gastrectomy unless it is suspected to be involved by the term survival after gastrectomy for gastric cancer is still not proven tumour (Degiuli et al, 1998). by RCTs. Moreover, the Dutch and British trials have shown The present study has also shown good survival data. The increased morbidity and mortality figures after D2 gastrectomy overall 5-year survival rate was 55%. Moreover, the disease-specific (Bonenkamp et al, 1995; Cuschieri et al, 1996). Potential reasons 5-year survival was 65%. Our results are almost equivalent to those for this unfavourable outcome include the lack of surgical reported by Sasako after 2541 extended gastrectomies performed at skilfulness/training and poor quality control, and the routine the National Cancer Center Hospital, Tokyo, during the period removal of the spleen and tail of the pancreas in total gastrectomy ‘1982–1991’ (66%) (Sasako et al, 1997, pp 223–248). Not only the (Cuschieri et al, 1996). overall survival rate but also the stage-specific survival rates after In our previous paper, we showed that it is possible to achieve D2 dissection were much better in this study than those of the D2 low morbidity and mortality after extended lymph node dissection, arm of the Dutch and MRC trials (Table 2). British Journal of Cancer (2004) 90(9), 1727 – 1732 & 2004 Cancer Research UK Survival of IGCSG D2 gastrectomy phase II study M Degiuli et al The discrepancy between our data and data from other Western Table 3 Relative experience of participating centres in Italian, British and series could be explained by differences in the patient population Dutch trials. or by differences in surgical technique. a b IGCSG DGCG MRC Regarding the patient populations, the eligibility criteria from the two large prospective randomised series are totally comparable No. of centres 9 80 322 to those adopted in our trial. No. of surgeons 9 pairs 11/85 32 With respect to the clinical and pathological stages, no major Duration of enrolment (years) 2.5 4 7 differences appear in the reported series apart from a clear No of patients 191 331 200 prevalence of early gastric cancer in the Japanese series. The Average no. of procedures/hospital/year 7 1.5 1 prevalence of early tumours (stage I disease) is close to 50% in the a b Dutch Gastric Cancer Group trial. Medical Research Council, British Trial. Japanese series, while it is 35.6% in our population, 36% in the Supervising/local surgeons. MRC series, 26% in the Dutch trial and 19.6% in an American patient care study (16). Siewert gives the figures for IA and IB stages, which are, respectively, 13.8 and 13.4% (3). In the present series, the number of patients with TNM stage less than III is substantial (106 patients, 55.4%) and might be partly responsible Table 4 Spleen and pancreas removal during total gastrectomies in for our good survival data. Italian, British and Dutch trials To avoid the confounding effect of stage migration, we should compare the results of series reporting D2 a b IGCSG no. (%) DGCG no. (%) MRC no. (%) dissection with each other. Our results are similar to those previously reported by Pacelli et al. (1993) in their retrospective Total gastrectomies 67 (100) 126 (100) 108 (100) trial and by Siewert et al (1993) in their prospective nonrando- Splenectomies 49 (73.1) 124 (98.4) 131 (121.2) mised trial. Pancreatectomies 10 (14.9) 98 (77.7) 113 (104.6) The main criticism that has been directed towards the a b c Medical Research Council, British trial. Dutch Gastric Cancer Group trial. A total of recent prospective randomised European trials has been 25 splenectomies performed during a distal gastrectomy. Five pancreatectomies the lack of experience of the surgeons participating in the performed during a distal gastrectomy. study. The contrast in postoperative mortality between the Dutch or British trials and our own study clearly demonstrated the danger of carrying out this procedure, let alone an RCT, without sufficient pretrial training. Clearly a one-arm study, equivalent to As already indicated, subset analysis of the Dutch the phase II study in medical treatment, is an appropriate and MRC trials documented that the higher morbidity in the D2 preliminary to a phase III trial of complex and potentially arm is mostly due to pancreas and spleen removal (Cuschieri et al, hazardous surgery. MS, who was supervisor of both the Dutch 1996). Hence, pancreas preservation was adopted as standard and the Italian study, believes that the Dutch study was flawed by procedure in D2 dissection in the present trial. Therefore, the early randomisation of patients, and the inclusion of many small- pancreas was removed only when it was suspected to be involved volume hospitals. It is suggested that a new surgical technique by the tumour (T4). Furthermore, during total gastrectomy, requiring not only surgical skills but also good experience in splenectomy was not carried out in patients with clinical T1 postoperative care should only be tested in an RCT after tumour (Table 4). completion of sufficient training to carry it out safely. In fact, After confirming the low mortality and acceptable morbidity of the reported perioperative mortalities in these two major RCTs on pancreas-preserving D2 dissection, we started a phase III trail, D2 dissection were over 10%. Pancreaticoduodenectomy for comparing D1 vs D2 in 1998. The survival results shown in this pancreatic cancer or radical oesophagectomy for oesophageal paper suggest the benefits of D2 dissection, although a statistically cancer are more surgically aggressive procedures than D2 significant survival advantage needs to be confirmed through this gastrectomy and are recommended to be performed exclusively new randomised phase III trial. The aim of this phase III trial is to in specialised centres. They do not carry a risk of hospital document an increase of survival in the D2 arm with acceptable mortality of over 10% in such centres (Altorki and Skinner, 1997; increase of morbidity and without increase of mortality. Gordon et al, 1998; Bottger and Junginger, 1999; Lerut et al, 1999; Tsiotos et al, 1999; Gouma et al, 2000; Karl et al, 2000). Postoperative mortality of over 10% is no longer acceptable in any kind of cancer surgery. ACKNOWLEDGEMENTS Our own experience correlates well with the data given by Parikh et al (1996) about the duration of the learning We acknowledge the contribution of Tiziano Allone, MD, for his curve for D2 dissection, which should be more than 15 procedures. assistance with the data collection and performing the statistics; we Each participating centre treated 15 to more than 25 patients also thank Alessandra Spitale, Franca Gilardi and the Registro (seven procedures per year on an average) (Table 3), and Tumori Piemonte for conducting the follow-up of the study cohort. in every centre each patient was always treated by the same This research is supported by the Comprehensive 10-year Strategy two surgeons. Therefore, each centre and each surgeon should for Cancer Control of the Ministry of Health, Labour and Welfare have reached an optimal experience level, acquiring sufficient of Japan. technical skills regarding intra- and postoperative care during this We also thank the following surgeons who took part in the trial trial. Our results support the argument for training the surgeons participating in data collection and clinical evaluation: Dario prior to the initiation of a clinical trial although, at a practical level, Andreone (Orbassano), Alessandro Balcet (Torino), Riccardo a study target of 700–1000 patients would be very difficult to Bussone (Torino), Lorenzo Capussotti (Torino), Gianruggero conduct, and it might take more than 10 years to recruit all the Fronda (Torino), Marcello Garavoglia (Novara), Mauro Garino patients. (Torino), Luigi Locatelli (Torino), Paolo Mello Teggia (Orbassa- We observed an overall postoperative in-hospital mortality of no), Mario Morino (Torino), Fabrizio Olivieri (Novara), 3.1%: this rate has been decreasing from 5.2% in 1994, to 2.11% in Fabrizio Rebecchi (Torino), Donatella Scaglione(Torino) and Tito 1995 and finally to 1.7% in 1996. While not statistically significant, Soldati (Biella). We thank Bruce Mann for assistance with the this trend supports the concept of a learning curve. manuscript. & 2004 Cancer Research UK British Journal of Cancer (2004) 90(9), 1727 – 1732 Clinical Clinical Survival of IGCSG D2 gastrectomy phase II study M Degiuli et al REFERENCES Altorki NK, Skinner DB (1997) Occult cervical nodal metastasis in Japanese Research Society of Gastric Cancer (1981a) The general rules for esophageal cancer: preliminary results of three-field lymphadenectomy. the gastric cancer study in surgery and pathology. Part I. 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British Journal of Cancer – Springer Journals

Published: Apr 6, 2004

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