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Oesophagogastric cancer: exploring the way to an individual approach
Stiekema, J.
Publication date
2015
Document Version
Final published version
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Citation for published version (APA):
Stiekema, J. (2015). Oesophagogastric cancer: exploring the way to an individual approach.
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ANNEMIEKE CATS ANKE M. KUIJPERS FRITS VAN COEVORDEN HENK BOOT
EDWIN P.M. JANSEN MARCEL VERHEIJ OLGA BALAGUE PONZ MICHAEL HAUPTMANN JOHANNA W. VAN SANDICK
SURGICAL TREATMENT RESULTS OF INTESTINAL
AND DIFFUSE TYPE GASTRIC CANCER
IMPLICATIONS FOR A DIFFERENTIATED
THERAPEUTIC APPROACH?
ABSTRACT Aim
To study the outcome of patients who were surgically treated for primary gastric cancer with specific attention to differences in treatment results for intestinal and diffuse type tumours.
Methods
All patients who underwent a potentially curative gastric resection between 1995 and 2011 in our institute were included. Patient, tumour and treatment characteristics were obtained retrospectively. Binary logistic and Cox regression models were used for multivariate analysis.
Results
A consecutive series of 132 patients was included. Median follow-up was 53 months. There were no significant differences between patients with intestinal (N = 62) versus diffuse type (N = 70) gastric cancer with regard to the proportion of patients who underwent (neo)adjuvant treatment. Postoperative mortality was 2%. Pathological T- and N-stage were significantly more advanced for patients with diffuse type tumours. There was a significant difference in the percentage of microscopically irradical resections (2% versus 24%, p < 0.001) and median overall survival (129 versus 17 months, p < 0.001) between patients with intestinal type tumours and those with diffuse type tumours. On multivariate analysis, diffuse type histology was the only factor significantly associated with an R1 resection. In a multivariate Cox regression model, diffuse type histology was a significant adverse prognostic factor for overall survival.
Conclusions
Striking differences were found between patients with diffuse type tumours and those with intestinal type tumours. These differences call for a differentiated approach in the potentially curative treatment of these two tumour types.
INTRODUCTION
Survival rates for gastric cancer in Asian countries are substantially better than those in Western countries.1 This has been attributed in part to higher incidence rates of gastric
cancer in Asia and the introduction of screening programs, which results in detection of neoplasia in earlier stages. Another explanation may be a more aggressive surgical approach with a higher lymph node yield in Asian countries. This possibly leads to stage migration or exerts a direct therapeutic effect and is performed without compromising the low postoperative mortality in these countries.2,3 However, also other factors, such
as tumour location and biology may play a role, i.e., the more frequent distal tumour location, the predominant intestinal type (according to Laurén’s classification4) and the
favourable response to adjuvant chemotherapy in Asian patients.1,5-7
In Western countries, the incidence of gastric cancer declined with a shift in tumour location from the distal to the proximal stomach and a change in histological subtype from intestinal to diffuse type adenocarcinomas.8,9 The declining incidence is more
prominent for distally located tumours and intestinal type gastric cancer, while the incidence of proximally located tumours and diffuse type gastric cancer has remained more or less stable.8
Despite the introduction of multimodality treatment regimes, the overall prognosis remains poor and has even worsened in several Western series.10,11
In order to evaluate the impact of tumour biology on the outcome of surgery, we have analysed the results of surgical treatment for primary gastric cancer in our institute, with special attention to differences in outcome between patients with intestinal type and those with diffuse type gastric cancer.
METHODS Patients
We selected all patients who underwent a potentially curative gastric resection for primary gastric adenocarcinoma between January 1995 and December 2011 in our hospital, which is a comprehensive cancer centre. Patient, tumour and treatment characteristics were retrieved from written and electronic patient files.
Diagnosis and staging
In all patients, diagnosis was assessed by oesophagogastroduodenoscopy and histological examination of subsequently obtained biopsy samples. Routine preoperative staging included computed tomography scan of chest and abdomen with oral and intravenous contrast and intravenous butylscopolammonium bromide for stomach relaxation. Endoscopic ultrasonography and, more recently, 18F-luorodeoxyglucose
positron emission tomography were also performed according to physician’s judgement. Staging laparoscopy was done when peritoneal dissemination was suspected by non-invasive diagnostic imaging results.
Histopathology
Histological subtype according to Laurén’s classification was documented for all tumours. Mixed-type tumours (N = 9) were listed as diffuse type gastric cancer. Resected tumours were staged according to the pathological (pTNM) classification of the American Joint Committee on Cancer, 7th edition.12 A pathological complete response after
neo-adjuvant treatment was graded as stage 0. A microscopically irradical (R1) resection, either proximal, distal or circumferential, was defined as the presence of tumour cells in the resection margins on standard microscopic examination or additional immunohistochemical staining with the anticytokeratine monoclonal antibody CAM 5.2. Surgical and (neo)adjuvant treatment
All patients were operated with an open surgical technique. Radical resection was the main objective when potentially curative treatment was installed. A partial gastrectomy was only performed in distally located tumours when a macroscopic margin of at least 6 cm could be obtained. A D2 lymph node dissection has become standard practice in our institute. In patients with significant co-morbidity and no signs of lymph node metastasis prior to or during surgery, a D1 lymph node dissection was performed.
(Neo)adjuvant chemotherapy has been administered for locally advanced tumours since 1998 and consisted of a regimen constisting of epirubicine, cisplatinum and continuous 5-fluorouracil intravenously.13 The latter was replaced by oral capecitabine in 2002.14
Adjuvant chemoradiotherapy has been part of several phase I-II trials conducted at our institute between 2000 and 2008.15,16 Since 2006, patients are preferably treated in
the international phase III CRITICS study (NCT00407186).17 In this study, patients with
resectable gastric cancer are randomised before the start of neoadjuvant chemotherapy between adjuvant chemotherapy and adjuvant chemoradiotherapy. As of 2007, patients with non-metastatic irresectable T4-tumours have been treated with neo-adjuvant chemoradiotherapy followed by surgery in the context of a feasibility study.
Surgical complications were graded according to the five-point scale as proposed by Dindo et al.18 Grade I complications (any deviation from the normal postoperative course
without the need for pharmacological treatment or intervention) were not recorded. When multiple complications occurred in one patient, only the most severe complication was recorded. Postoperative mortality was defined as in-hospital death and/or death within 30 days. After treatment, patients were followed at 3-4 month intervals during the first two years, and at 6-month intervals thereafter. Diagnostic investigations were performed upon the occurrence of symptoms or according to the clinical trial protocols. In the present study, tumour recurrences were recorded as locoregional, peritoneal or distant. Locoregional recurrence was defined as recurrent disease at the primary tumour site, including the anastomosis and the regional lymph node basins. Peritoneal tumour deposits and/or malignant ascites were recorded as peritoneal carcinomatosis. When locoregional recurrence and/or peritoneal carcinomatosis was detected simultaneously with distant visceral metastasis, the site of tumour recurrence was classified as distant. Follow-up data were collected until death or January 2012.
Statistics
Comparisons between patients with intestinal type and those with diffuse type gastric cancer were done using Pearson’s X2 or Fisher’s exact test for nominal variables, the X2
test of trend for ordinal variables and the Mann-Whitney U test for continuous variables. Overall survival was defined as the time from surgery to the date of death from any cause or to the date of last follow-up. Survival was illustrated by Kaplan-Meier curves and compared with the log rank test. A binary logistic regression analysis and Cox proportional hazards model were used for multivariate analysis. The proportional hazards assumption was tested and no evidence for non-proportionality was found. All tests were 2-sided and a P value < 0.05 was considered significant. SPSS statistical software (SPSS, Chicago,IL, version 17.0) was used for analysis.
RESULTS Patients
Between 1995 and 2011, 210 consecutive patients underwent some type of gastric resection for a variety of disease entities. Only patients with a potentially curative gastric resection for primary gastric carcinoma were included (N = 132). Patients with gastrointestinal stromal cell tumours (N = 47), leiomyosarcoma (N = 2), lymphoma (N = 1), recurrent gastric cancer (N = 2), palliative resection (N = 21) or prophylactic resection for hereditary diffuse gastric cancer (N = 5) were excluded. Median follow-up for living patients was 53 months (range 1 – 184 months). One patient was lost to follow-up after 48 months. Pre-treatment characteristics are presented in table 1. Patients with intestinal type tumours (N = 62) were more frequently male and were usually older than patients with diffuse type tumours (N = 70). Tumour location differed significantly between the two histological subtypes. Intestinal type tumours as opposed to diffuse type tumours were equally spread throughout the three stomach regions, while diffuse type carcinomas more frequently involved the whole stomach. Frequency and types of (neo)adjuvant therapies were equally distributed among the two patient groups (Table 1).
Surgical treatment
Surgical features and histopathological staging are summarized in Table 2. The proportion of total gastrectomies was higher in the group of patients with diffuse type gastric cancer, but the difference was not statistically significant. The extent of lymph node yield was comparable between the two groups. R1 resections were significantly more frequent in patients with diffuse type gastric cancer. In these patients (N=17; 24%), the duodenal margin was involved in eight patients, the oesophageal margin in six patients and both margins in three patients. In the group of patients treated with primary surgery (N=56), 5 patients (9%) had an R1 resection, compared to 13 patients (18%) in the group of patients treated with neoadjuvant chemotherapy (N=73). In a binary logistic regression analysis with tumour location, histological subtype, extent of gastric resection and pathological T- and N-stage, only diffuse histological subtype was significantly associated with an R1 resection (Odds ratio (OR) 16.093; 95% CI 2.025 – 127.900, p = 0.009).
Table 1. Pre-‐treatment characteristics and type of (neo)adjuvant treatment
ASA: American Society of Anaesthesiologists
Numbers between parentheses are percentages, unless otherwise specified * Pearson X2 test
** X2 test of trend ± Mann-‐Whitney U-‐test Variable N (%) All N = 132 Intestinal type N (%) N = 62 Diffuse type N (%) N = 70 P-value Gender - Male - Female 77 (58) 55 (42) 44 (71) 18 (29) 33 (47) 37 (53) p = 0.006*
Age in years (median, range) 63 (28 – 85) 65 (39 – 84) 59 (28 – 85) p = 0.026±
ASA-classification I II III 54 (41) 62 (47) 16 (12) 27 (44) 28 (45) 7 (11) 27 (39) 34 (48) 9 (13) p = 0.576** Tumour location - Upper third - Middle third - Lower third - Overlapping 24 (18) 46 (35) 49 (37) 13 (10) 18 (29) 20 (32) 21 (34) 3 (5) 6 (9) 26 (37) 28 (40) 10 (14) p = 0.011* Neo-adjuvant treatment - None - Chemotherapy - Chemoradiotherapy 56 (43) 73 (55) 3 (2) 26 (42) 34 (55) 2 (3) 30 (43) 39 (56) 1 (1) p = 0.787* Adjuvant treatment - None - Chemotherapy - Chemoradiotherapy 84 (64) 26 (20) 22 (16) 43 (69) 11 (18) 8 (13) 41 (59) 15 (21) 14 (20) p = 0.402*
Table 1. Pre-treatment characteristics and type of (neo)adjuvant treatment
ASA: American Society of Anaesthesiologists
Numbers between parentheses are percentages, unless otherwise specified * Pearson X2 test
** X2 test of trend
± Mann-Whitney U-test
Pathological tumour and nodal stage were more advanced in patients with diffuse type tumours than in those with intestinal type tumours. Postoperative mortality was 2% for all patients. The overall complication rate (i.e., grade II-IV complication) was 28%. Most common were pulmonary complications (8%) and anastomotic leakage (5%). Seventeen patients (13%) had a postoperative complication requiring surgical or radiological re-intervention. Median hospital stay was 13 days (range 6 – 72 days).
Survival
For all patients, three and five-year overall survival rates were 56% and 46%. The median overall survival was 49 months (Fig. 1a). There was a significant difference in median overall survival between patients with intestinal type tumours and those with diffuse type tumours (129 versus 17 months, p < 0.001, Fig. 1b). After exclusion of patients who underwent an R1 resection (N=18), this survival difference remained significant (129 versus 23 months, p = 0.003). In the group of patients with diffuse type gastric cancer, median overall survival was significantly better for patients with an R0 resection compared to those with an R1 resection (23 versus 8 months, p = 0.005). In a multivariate analysis, diffuse histological type was an adverse prognostic factor for overall survival
Table 2. Surgical and pathological results
R0, microscopically radical resection; R1, microscopically irradical resection
#Staging according to the pathological (pTNM) classification of the American Joint Committee on Cancer 7th edition12
##Classification of postoperative complications according to Dindo et al.17
* Pearson X2 test
± Mann-Whitney U-test ˠ Fisher’s exact test ** X2 test of trend
Numbers between parentheses are percentages, unless otherwise specified
Table 2. Surgical and pathological results
R0, microscopically radical resection; R1, microscopically irradical resection
#Staging according to the pathological (pTNM) classification of the American Joint Committee on Cancer 7th
edition12
##Classification of postoperative complications according to Dindo et al.17
* Pearson X2 test ± Mann-‐Whitney U-‐test
ˠ Fisher’s exact test ** X2 test of trend
Numbers between parentheses are percentages, unless otherwise specified
Variable N (%) All N = 132 Intestinal type N (%) N = 62 Diffuse type N (%) N = 70 P-value
Extent of gastric resection - Partial gastrectomy
- Total gastrectomy 62 (47) 70 (53) 33 (53) 29 (47) 29 (41) 41 (59) p = 0.175*
Number of lymph nodes evaluated (median, range) 17 (1 – 49) 15 (1 – 49) 18 (3 – 42) p = 0.460 ± Radicality of resection - R0 - R1 114 (86) 18 (14) 61 (98) 1 (2) 53 (76) 17 (24) p < 0.001ˠ pT stage# - T0 - 1 - T2 - T3 - T4a - T4b 27 (21) 21 (16) 56 (42) 17(13) 11 (8) 18 (29) 14 (23) 25 (40) 2 (3) 3 (5) 9 (13) 7 (10) 31 (44) 15 (21) 8 (12) p < 0.001** pN stage# - N0 - N1 - N2 - N3 71 (54) 24 (18) 21 (16) 16 (12) 38 (61) 14 (23) 5 (8) 5 (8) 33 (47) 10 (14) 16 (23) 11 (16) p = 0.019** Postoperative complications## - None/grade I - Grade II - Grade III - Grade IV - Grade V 92 (70) 18 (14) 17 (13) 2 (1) 3 (2) 41 (66) 9 (15) 10 (16) 0 (0) 2 (3) 51 (73) 9 (13) 7 (10) 2 (3) 1 (1) p = 0.443**
(Hazard ratio (HR) 2.317; 95% CI 1.188 – 4.519, p = 0.014, Table 3). Other significant prognostic factors were pathological lymph node stage (p < 0.005), radicality of resection (p = 0.014) and adjuvant therapy (yes versus no; p < 0.001).
Recurrence
Tumour recurrence patterns were evaluated only in patients who had undergone a microscopically radical resection (N=114). Recurrent disease was more frequently observed in patients with diffuse type tumours than in those with intestinal type tumours (49% versus 20%, p < 0.001). The first site of tumour recurrence is shown in Table 4. In the group of patients with recurrent diffuse type gastric cancer (N=26), 21 patients (81%) had locoregional recurrence (with or without simultaneous peritoneal carcinomatosis) or peritoneal carcinomatosis only.
Figure 1a. Overall survival for all patients who underwent a potentially curative resection for gastric cancer between 1995 and 2011 (including postoperative mortality)
Figure 1b. Overall survival for patients who underwent a potentially curative resection for gastric cancer between 1995 and 2011 according to histological subtype (including postoperative mortality).
DISCUSSION
In this study, we analysed short-term and long-term outcome of potentially curative gastric cancer surgery over a period of 16 years in our institute. Postoperative complications were seen in 28% of patients and postoperative mortality was 2%. Three and five-year overall survival rates for all patients were 56% and 46%. There was a striking difference in the percentage of microscopically irradical resections (2% versus 24%) between patients with intestinal and diffuse type tumours. On multivariate analysis including various clinicopathological factors, diffuse type histology was the only factor significantly associated with an R1 resection. There also was an impressive difference between intestinal type and diffuse type gastric cancer in the median overall survival (129 versus 17 months). After exclusion of R1 resected patients, this difference remained significant (129 versus 23 months). In a multivariate analysis, diffuse histological type was an independent prognostic factor for overall survival. Other significant prognostic factors were postoperative nodal stage, radicality of the resection and adjuvant treatment. Irradical resections
Five-year survival rates after surgical resection of gastric cancer in European studies vary between 23.0% and 54.7%.10,19-21 This variation can be partly explained by differences
in inclusion criteria and case-mix factors. Although a comparison with our study is hampered by the latter, we believe the results regarding survival of the current study are in line with other patient series.
In a recent systematic review on predictors of tumour positive margins in gastric cancer surgery, the R1 resection rate in studies which excluded R2 resections varied between 2% and 22%.22 Heterogeneity in data collection, inclusion criteria and patient, tumour and
treatment characteristics made comparisons between the studies in this review difficult. In only one study, the association with Laurén’s classification was tested in a multivariate model and in this Italian study it was also found that irradicality was independently associated with diffuse type gastric cancer.23 Whether neoadjuvant treatment can
reduce the number of irradical resections is unclear. In the MAGIC-trial, patients were randomised for perioperative chemotherapy and surgery versus surgery alone. Following preoperative chemotherapy the curative resection rates were similar between patients that were treated with and without preoperative chemotherapy (69% versus 66%).19 The
R1 resection rate in these groups is not specified nor is the Laurén classification. In our study, the R1 resection rate was 9% in patients who underwent primary surgery versus 18% in patients treated with neoadjuvant chemotherapy. However, one can not exclude the impact of patient selection on these results, as the results are not corrected for pre-treatment case-mix factors.
The detrimental effect of an irradical resection on survival has been described in many studies.22 Also in the current series, an R1 resection was an independent adverse prognostic
factor for survival. More extensive surgery and re-operation to obtain an R0 resection are subject of debate and opinions in literature are conflicting. In the current series, more
Table 3. Cox regression model of prognostic factors for overall survivalTable 3. Cox regression model of prognostic factors for overall survival Number of
patients Univariate Multivariate
HR (95% CI) p - value HR (95% CI) value p –
Age in years - < 60 - 60 - 70 - > 70 50 39 40 1.0 0.752 (0.403 – 1.404) 1.265 (0.663 – 2.413) 0.324* 0.371 0.475 Sex - Male - Female 77 55 1.321 (0.778 – 2.242) 1.0 0.303 ASA - ASA I - ASA II - ASA III 52 62 15 1.0 1.135 (0.645 – 1.995) 1.583 (0.651 – 3.849) 0.359* 0.661 0.311 Tumour location - Upper third - Middle third - Lower third - Diffuse 24 46 46 13 1.0 0.812 (0.367 – 1.796) 1.179 (0.544 – 2.554) 2.443 (0.908 – 6.576) 0.098* 0.607 0.677 0.077 Histological subtype ˠ - intestinal type - diffuse type 60 69 1.0 3.437 (1.905 – 6.202) < 0.001 1.0 2.317 (1.188 – 4.519) 0.014
Extent of gastric resection
- partial gastrectomy
- total gastrectomy 59 70 0.733 (0.425 – 1.263) 1.0 0.263
Number of lymph nodes evaluated - < 15 - 15 - 24 - >= 25 53 47 29 1.0 0.787 (0.396 – 1.561) 0.805 (0.317 – 2.045) 0.162* 0.492 0.649 pT stage# - T0 - 1 - T2 - T3 - T4a - T4b 26 21 55 11 17 1.0 1.819 (0.551 – 6.012) 4.690 (1.767 – 12.449) 5.319 (1.639 – 17.259) 6.029 (1.803 – 20.159) < 0.001* 0.326 0.002 0.005 0.004 1.0 1.254 (0.356 – 4.418) 3.260 (1.076 – 9.882) 1.676 (0.417 – 6.731) 1.258 (0.235 – 6.720) 0.060* 0.724 0.037 0.467 0.788 pN stage# - N0 - N1 - N2 - N3 68 24 21 16 1.0 1.362 (0.616 – 3.012) 4.397 (2.131 – 9.073) 7.053 (3.045 – 16.336) < 0.001* 0.445 < 0.001 < 0.001 1.0 1.618 (0.685 – 3.822) 2.912 (1.189 – 7.131) 5.843 (2.165 – 15.773) 0.005* 0.273 0.019 < 0.001 Radicality - R0 - R1 111 18 1.0 5.136 (2.598 – 10.152) < 0.001 1.0 2.700 (1.224 – 5.957) 0.014 Adjuvant therapy - No - Yes 84 48 0.357 (0.164 – 0.774) 1.0 0.009 0.176 (0.074 – 0.417) 1.0 < 0.001
In-hospital deaths and/or deaths within 30 days (N = 3) were excluded from this analysis. Stratification according to year of treatment was performed in this analysis.
HR, Hazard ratio; CI, Confidential interval ASA, American Society of Anaesthesiologists;
R0, microscopically radical resection; R1, microscopically irradical resection ˠ According to Laurén’s classification
#Staging according to the pathological (pTNM) classification of the American Joint Committee on Cancer, 7th edition12
Table 4. Tumour recurrence patterns in patients who underwent an R0 resection
In two patients the exact site of recurrence was unknown # including patients with simultaneous peritoneal carcinomatosis.
* including patients with simultaneous locoregional recurrence and/or peritoneal carcinomatosis.
First site of tumour recurrence Intestinal type N (%) (N = 61) Diffuse type N (%) (N = 53) None 49 (80) 27 (51) Locoregional recurrence # 8 (13) 11 (21) Peritoneal carcinomatosis only 0 (0) 8 (15) Distant metastasis * 3 (5) 6 (11) Table 4. Tumour recurrence patterns in patients who underwent an R0 resection
In two patients the exact site of recurrence was unknown # including patients with simultaneous peritoneal carcinomatosis. * including patients with simultaneous locoregional recurrence and/or peritoneal carcinomatosis.
radical surgery would have been a clear option, if R1 resections had occurred after partial gastrectomy at the intra-gastric resection margin. But, microscopic irradicality was only seen at the duodenal and/or oesophageal margin. Extending the operation to a distal oesophagectomy following intra-operative frozen section results of the proximal margin can only be considered in a patient who can tolerate a thoracotomy in addition to the laparotomy. On the other side, the addition of a pancreaticoduodenectomy to reach a free distal margin carries considerable surgical morbidity.24 Another strategy to improve
outcome could be the administration of adjuvant chemoradiotherapy in case of an R1 resection. In a retrospective study by Dikken et al., patients with an R1 gastric resection and adjuvant chemoradiotherapy had a better overall survival than those who did not receive adjuvant chemoradiotherapy.25 Randomised data on adjuvant chemoradiotherapy after
gastric cancer surgery are only available for R0 resected patients.26,27 In oesophageal
cancer, neoadjuvant chemoradiotherapy increases the R0 resection rate as compared to primary surgery.28 As for gastric cancer, this strategy has so far only been tested in
phase I-II studies with small patient numbers, but results regarding R0 resection rates are promising.29-31
Histological subtypes
In previous studies, diffuse type histology has been described as an adverse prognostic factor.10,32,33 In our series, median overall survival for patients with diffuse type tumours
(17 months) was significantly worse compared to those with intestinal type tumours (129 months), even after an R0 resection. Also in a recent German patient series, median overall survival for patients with diffuse type gastric cancer after an R0 resection was only 17 months.34 The site of tumour recurrence was often locoregional and/or limited to the
peritoneal cavity. In our series, this holds true for 73% of patients with diffuse type gastric cancer and recurrent disease after an R0 resection. The finding is in concordance with
earlier reports,35-37 which were performed in a period in which multimodality treatment
was mainly investigational. Although in our study, the majority of patients was treated with chemo(radio)therapy in addition to surgery, outcome is still poor, specifically for patients with diffuse type tumours. Administration of adjuvant therapy was a favourable prognostic factor in our multivariate analysis. There was, however, heterogeneity in the used regimes and the data are retrospective. Therefore, this result needs to be interpreted with extreme caution. In the recently published update of the Intergroup 0116 randomised study substantiating the benefit of adjuvant chemoradiotherapy in resected gastric tumours, the subgroup of patients with diffuse type tumours did not benefit from adjuvant chemoradiotherapy.38 These results also need to be interpreted
with caution given the unplanned nature of the subset analysis and the relatively small size of this subgroup. Others have evaluated the prognostic significance of histological tumour regression rate to neoadjuvant cisplatinum-based chemotherapy and found that diffuse type tumours showed less regression than intestinal type tumours.39 In
a multivariate analysis, histological tumour regression proved to be independent prognostic factors for survival. Although this was also a retrospective study, these results underscore the importance of patient stratification with respect to histological subtype in clinical trials on (neo)adjuvant treatment of gastric cancer. The classification of gastric cancer subtypes differs between pathologists and thus between papers. Two commonly used systems are the Laurén classification and World Health Organization (WHO) classification.40 These systems are not interchangeable, but there is some overlap:
adenocarcinoma with a signet ring cell subtype is associated with diffuse histological type according to Laurén, whereas other histological subtypes are more often intestinal type tumours.41,42 In two recent studies, the prognostic impact of signet ring cell histology
was studied with contradictory results.43,44
Additional treatment
Given the high frequency of locoregional and peritoneal tumour recurrence (without distant metastatic disease), hyperthermic intraperitoneal chemotherapy (HIPEC) is a plausible additional treatment option. Recently, in a small Chinese randomised controlled trial comparing cytoreductive surgery with and without HIPEC in patients with peritoneal carcinomatosis from gastric cancer, a survival advantage was observed for patients treated with HIPEC.45 Other studies are mostly prospective case series with a
large heterogeneity in patient population.46 The multi-national GASTRICHIP study, which
includes gastric cancer patients with a peritoneal lavage positive for tumour cells, might shed further light on the role of HIPEC in gastric cancer.
Limitations
There are some limitations to the current study. The retrospective design with the inclusion of a selected patient group over a time period of 16 years may have introduced bias. Furthermore, the two patient groups with intestinal and diffuse type tumours were not balances regarding stage of disease. To account for these intrinsic differences and
possible changes in treatment over time, we performed a multivariate analysis which was stratified according to the year of treatment. Another option to balance covariates between populations is a case match study, which requires a large patient population. The prospective upper GI cancer audit (http://www.clinicalaudit.nl/duca/), which started in 2011 might be a valuable source for such future studies.
Conclusions
It can be concluded that although short-term clinical outcome results of gastric cancer resection were acceptable in this series, the rate of microscopically irradical resections was high, specifically for diffuse type tumours. Even in patients with R0 resected diffuse type tumours, recurrence rates were high. In a multivariate analysis, diffuse type histology was identified as an adverse prognostic factor. These differences call for a differentiated approach in the potentially curative treatment of intestinal and diffuse type gastric cancer.
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