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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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SABRINE KOL ANNEMIEKE CATS AMIR T. YAZDI
FRITS VAN COEVORDEN JOHANNA W. VAN SANDICK
SURGICAL TREATMENT OF GASTROINTESTINAL
STROMAL TUMOURS LOCATED IN THE
ABSTRACT Background
Imatinib has changed the treatment of gastrointestinal stromal tumours (GISTs). Preoperative imatinib treatment can be administered to patients with locally advanced disease to reduce the risk of incomplete resection, tumour spill and lessen the extent of resection. In metastatic GIST, surgery follows imatinib in responding patients with resectable disease. In this study, the outcome of surgically treated patients with a gastric GIST with and without preoperative imatinib was investigated.
Methods
Patients surgically treated for a gastric GIST at our institute between 1999 and 2011 were included. Patient data were retrieved from a prospectively maintained database.
Results
A consecutive series of 47 patients was identified: 17 patients were treated with primary surgery (group 1) and 30 patients received imatinib prior to surgery (group 2). Preoperative imatinib led to a 33% reduction in tumour size. All patients in group 1 and 23 patients (77%) in group 2 had a complete resection (R0) without tumour spill. At a median follow-up of 30 months, four patients in grofollow-up 2 had died of GIST. In these 4 patients, either the resection had been irradical or tumour spill had occurred, and 3 of them had radiological progressive disease at the time of surgery.
Conclusions
In this surgical series of gastric GIST patients, preoperative imatinib led to a major reduction in tumour size. Irradical resection, tumour spill and progressive disease at the time of surgery were associated with poor prognosis.
INTRODUCTION
Gastrointestinal stromal tumours (GISTs) originate from the interstitial cells of Cajal and arise throughout the gastrointestinal tract. The majority of GISTs is found in the stomach (60-70%) and small bowel (20-25%).1 Traditionally, the outcome after surgical
resection of voluminous GISTs has been poor and only patients with small, localised and low grade tumours reached long term survival.2 The introduction of the selective
tyrosine-kinase inhibitor (TKI) imatinib has significantly improved the prognosis of patients with unresectable or metastatic GIST.3-4 Adjuvant imatinib therapy has been
shown to increase recurrence free survival. And, in a recent trial, 3-year adjuvant treatment in high risk GISTs improved recurrence free and overall survival compared to 1-year imatinib administration following surgical resection after a median follow-up of 54 months.5 Preoperative imatinib treatment can be considered in case of locally
advanced or marginally resectable disease, i.e. when the risk of incomplete resection, tumour spill or significant postoperative morbidity (due to multiple organ resections) is high. The definitive role of preoperative imatinib in locally advanced and metastatic GIST is yet to be established and up till now has only been under investigation in small single institution trials with relatively short follow-up and with GISTs arising in different parts of the gastrointestinal tract. Two of these studies suggested that only GISTs responsive or stable to neoadjuvant imatinib benefitted surgical resection. Available studies almost invariably contain patients with GISTs at various locations.6-9 Prognosis of GISTs,
however, also depends on tumour location. Patient series that involve exclusively gastric GISTs are rare and contain a very limited number of patients treated with preoperative imatinib.10 The aim of the present study was to analyze the outcome of patients who
underwent surgical resection for a gastric GIST with or without preoperative imatinib treatment at our institute. To our knowledge, this is currently the largest patient series with a primary gastric GIST treated with preoperative imatinib.
METHODS
From a prospective database of GIST patients, all patients with a primary GIST of the stomach who underwent surgical resection were identified. Surgery was performed between January 1999 and December 2011. In all patients, diagnosis was confirmed by positive CD117, CD34 and/or DOG-1 (after 2007) immunohistochemical staining. In all patients treated with preoperative imatinib, GIST diagnosis was confirmed prior to the start of treatment. Mutation analysis of KIT and PDGFRα was performed from 2005 and on, when preoperative or adjuvant treatment with TKI therapy was considered. Standard diagnostic work-up involved computed tomography scan (CT-scan) and, from 2004, fluorodeoxyglucose positron emission tomography (FDG-PET). Tumour samples for histopathological confirmation of GIST were obtained by endoscopy or ultrasound/ CT-guided needle biopsy. Each patient was discussed in a multidisciplinary sarcoma board. Patients with restricted localised disease were treated with primary surgery.
From 2002, imatinib was available in our institute. In case of locally advanced disease, resectability was evaluated by surgeons with extensive experience with GIST treatment. When tumours were considered marginally resectable due to tumour size, surgically unfavourable tumour location or possible invasion of surrounding organs, treatment with imatinib (400 mg per day) was started. Also in patients with metastatic disease, preoperative treatment with imatinib was started. In case of non-responding disease or the presence of an exon 9 KIT mutation, the dosage was increased to 800 mg per day. In patients with non-metastatic disease, preoperative imatinib treatment was continued for 6 – 12 months, or until radiologic progression occurred. Response to preoperative treatment was evaluated using CT-scan and/or FDG-PET every two months. In the absence of general guidelines for patients with metastatic disease, the duration of preoperative treatment was discussed in the multidisciplinary sarcoma board. For the purpose of this study, all CT-scans were reviewed by an expert radiologist (A.Y.) according to the criteria proposed by Choi et al.10-11 Following this, a patient was grouped into one of three groups:
radiologic responsive disease, stable disease or progressive disease prior to surgical resection. Surgery of the stomach consisted of a wedge resection, partial gastrectomy or total gastrectomy. Additional organ resection was performed only in case of direct tumour invasion. Postoperative complications were graded according to the five-point scale as proposed by Dindo and Clavien12. Grade I complications were not recorded.
Post-operative mortality was defined as in-hospital death and/or within 30-days after surgery. Tumour-free resection margins were classified as R0-resection. A microscopic or macroscopic irradical resection was defined as R1- or R2-resection, respectively. Adjuvant imatinib was administered in patients with intermediate or high-risk tumours (diameter > 5 cm and/or a mitotic count > 5/50 HPF), either in the context of a clinical trial (EORTC 62024), or based on risk assessment tables by Fletcher,13 Joensuu,14 or more
recently according to the nomogram of risk assessment by Gold et al.15 Follow-up data were collected until January 2012.
Statistics
Differences between proportions were tested with Fisher’s exact test or the chi-square test as appropriate. Continuous data was presented as median (range) and compared with the Mann-Whitney U or Wilcoxon’s signed ranks test. Overall survival was calculated from the date of surgery. Kaplan-Meier and log rank analyses were performed using SPSS statistical software (SPSS, Chicago,IL version 17.0). All tests were 2-sided and a P value < 0.05 was considered statistically significant.
RESULTS
Patient and tumour characteristics
From our database, 47 surgically treated patients with a GIST of the stomach were identified. Of these 47 patients, 17 patients underwent primary surgery (group 1) and 30 patients were operated after preoperative imatinib treatment (group 2). Patient and
tumour characteristics are presented in Table 1. All patients in group 1 had localised disease. Seven patients in group 2 had metastatic disease, consisting of liver metastasis in 5 patients, diffuse peritoneal metastasis in one patient and both liver and peritoneal metastases in another patient. Median size of the primary tumour was smaller in patients treated primary surgery compared to those treated with preoperative imatinib (50 versus 135 mm, p < 0.001). Tumour size in the surgical resection specimen in patients treated with primary surgery corresponded well with the size on the diagnostic CT. Median duration of preoperative imatinib treatment was 8.4 months (range 3.3 – 54.9). Preoperative imatinib treatment significantly reduced tumour size in the surgical resection specimen by 33% to 90 mm (Figure 1, p < 0.001).
Table 2 shows histopathological and molecular characteristics. In one patient with a CD117 and CD34 negative tumour on both preoperative biopsies and the resection specimen, GIST diagnosis was confirmed by positive DOG1 staining. Mutation genotypes of KIT en PDGFRα were known in 10 of 17 (59%) patients treated with primary surgery and in 19 of 30 (63%) patients treated with preoperative imatinib. A mutation in KIT or PDGFRα was present in 90% of patients in whom a mutation analysis was performed (26 of 29 patients). Mutations in exon 11 of KIT were most common (20 of 29 patients).
Table 1. Patient and tumor characteristics
Primary surgery (N = 17) Group 1 Preoperative imatinib (N = 30) Group 2 P N % N % Sex - Male - Female 8 9 47% 53% 22 8 73% 27% 0.114* Age (years) - Median (range) 57 (25-77) 58 (28-77) 0.807# Extent of disease - Localised - Metastatic 17 0 100% 0% 23 7 77% 23% 0.039* Location of primary tumor
- Cardia - Fundus - Corpus - Antrum 3 4 8 2 18% 24% 47% 11% 3 4 21 2 10% 13% 70% 7% 0.330**
Primary tumor size (mm)a
- Median (range) 50 (15-90) 135 (30-290) < 0.001#
a Tumor size at diagnostic CT-scan
* Fisher’s exact test
** Chi-square test
# Mann-Whitney U test
Table 1. Patient and tumour characteristics
a Tumour size at diagnostic CT-scan
* Fisher’s exact test ** Chi-square test # Mann-Whitney U test
Figure 1. Primary tumour size on diagnostic CT-scan versus tumor size in surgical resection specimen
Surgical treatment
In Figure 2, the progression of the patient cohort from the current study is outlined. On the last response evaluation prior to surgical resection, 19 patients had radiological responsive disease, 6 patients had stable disease and 5 patients showed progressive disease. Surgical treatment characteristics are presented in Table 3. In patients treated with preoperative imatinib, additional organ resections included resection of the transverse colon (4 patients), spleen (2 patients), transverse colon and spleen (1 patient) and transverse colon, spleen and pancreatic tail (3 patients). Liver metastases were treated with intra-operative radio frequency ablation in 6 patients. Postoperative complications (grade 2 or 3) were only seen in patients treated with preoperative imatinib and included intra-abdominal abscesses (3 patients), haemorrhage (2 patients) and pneumonia (1 patient). There were no grade 4 or 5 complications. An R0-resection was achieved in all patients treated with primary surgery and in 24 of 30 patients (80%) in the preoperative treatment group. One patient had microscopic disease at the resection margin (R1) and tumour spill occurred during surgery. In this patient, the tumour also involved the transverse colon, spleen and pancreatic tail. Two patients had diffuse peritoneal disease (R2). In 3 other patients, tumour spill occurred during the operation, but the resection margins were free at pathological examination. The tumour sizes in the resection specimen of these 3 patients were 100, 110 and 300 mm respectively.
Table 2. Histopathological tumour characteristics
Table 2. Histopathological tumor characteristics Primary surgery (N = 17) Group 1 Preoperative imatinib (N = 30) Group 2 N % N % CD 117 - Positive - Negative 16 1 94% 6% 30 0 100% 0% CD 34 - Positive - Negative - Unknown 15 1 1 88% 6% 6% 26 3 1 87% 10% 3% DOG 1a - Positive - Negative - Unknown 4 0 13 24% 0% 76% 5 0 25 17% 0% 83% Mutation - KIT exon 11 - KIT exon 9 - PDGFRα exon 18 Wild-type Unknown - Insufficient material - Not performed 6 - 3 1 - 7 35% - 18% 6% - 41% 14 1 2 2 8 3 46% 3% 7% 7% 27% 10%
a DOG 1 staining was performed in more recent years (2007 – 2011)
a DOG 1 staining was performed in more recent years (2007 – 2011)
Adjuvant treatment
Adjuvant imatinib was administered in two patients in the context of a clinical trial (EORTC 62024) and in 19 patients based on risk assessment tables by Fletcher,13 Joensuu14 or Gold
et al.15 The median duration of adjuvant treatment was 18 months (range 1 – 72 months).
Survival
Median follow-up was 30 months for all patients (1 – 135 months). Two patients were lost to follow-up. None of the patients in the primary surgery group died of GIST. Two of these patients died from unrelated causes. The one- and three-year postoperative survival in group 1 was 94%.
Four patients treated with preoperative imatinib died of progressive disease between 7 and 14 months after surgery. All four patients had either an irradical (R1 or R2) resection or intra-operative tumour spill and had local disease recurrence. Synchronous metastatic disease was seen in two of four patients. The one- and three-year postoperative survival rates in the group of patients treated with preoperative imatinib were 90% and 87%, respectively.
Figure 2. Flow diagram showing the progression of the cohort of gastric GIST patients (N = 47)
*An irradical resection includes a microscopically (R1) or macroscopically (R2) irradical resection and/or tumor spill
Figure 3 shows disease specific survival rates according to radicality of the resection. Two patients with an irradical resection were still alive at the time of analyses. One of these patients had diffuse peritoneal disease, but no vital tumour was found in both the resection specimen as in a peritoneal biopsy. Tumour spill occurred in the other patient and a partial response was seen in the resection specimen. All patients with an irradical resection or tumour spill received adjuvant imatinib.
In Figure 4, duration of follow-up is shown for patients treated with preoperative imatinib, grouped according to the radiological response prior to surgery. Four of five patients with radiologic progressive disease at the moment of surgery had disease recurrence during follow-up. Three of these patients died of progressive disease. One of these patients had metastatic disease consisting of peritoneal metastases.
DISCUSSION
The treatment of GIST patients has profoundly changed since the introduction of the tyrosine kinase inhibitor imatinib. It is currently the treatment of choice in patients with metastatic GIST and its value in the adjuvant setting has been proven in two large randomised trials.6, 16 The role of imatinib treatment prior to surgery has not fully been
established yet. Our results confirm that primary surgical resection is an excellent treatment for restricted, localised gastric GISTs.
Preoperative imatinib can be administered in two different clinical settings. In locally advanced disease, the rationale of imatinib is to decrease the chance of intra-operative tumour rupture and to reduce the extent of resection. In metastatic, unresectable disease, preoperative imatinib treatment may render patients, who respond to treatment, eligible for surgery. Before start of imatinib treatment, a histopathological diagnosis of GIST has to be obtained. Currently, diagnosis on biopsy samples using immunohistochemical
markers (CD117 and CD34) is considered common practice, but in 5% of GIST patients these markers are negative.17 In one patient in this study with negative CD117 and CD34
immunohistochemical staining, a diagnosis of GIST could be confirmed prior to surgery by DOG1 staining.17 This important additional molecular marker has a reported higher
sensitivity,18 which was 100% in our series.
In a large retrospective study by Takahashi et al., tumour rupture during surgery for GISTs at various locations was identified as an adverse prognostic factor.19 In a series
by Hohenberger et al., nearly all patients developed tumour recurrence after tumour rupture.20 In our series, surgical resection was complicated by tumour spill in none of
the patients treated with primary surgery and in 4 of 30 patients (13%) treated with preoperative imatinib. The present results support that imatinib can significantly reduce tumour size of gastric GISTs. Shrikhande et al. compared the treatment option of 29 GIST patients based on pre-operative imaging studies before imatinib treatment with the surgical procedure after imatinib. They concluded that tumour downsizing enabled more conservative surgical treatment.21 Also, one may expect that this leads to a decreased risk
Table 3. Surgical characteristics
RFA: Radiofrequency ablation R0: Microscopically radical resection R1: Microscopically irradical resection R2: Macroscopically irradical resection
a Postoperative complications were graded according to the five-point scale as
proposed by Dindo and Clavien12. Grade 1 complications were not recorded. b Percentages exceed 100% because one patient had an R1 resection and tumour spill.
* Fisher’s exact test ** Chi-square test
Table 3. Surgical characteristics
Primary surgery (N = 17) Group 1 Preoperative Imatinib (N =30) Group 2 P N % N %
Type of gastric resection - Wedge resection - Partial gastrectomy - Total gastrectomy 7 10 0 41% 59% 0% 4 22 4 13% 74% 13% 0.045**
Additional organ resection - Yes - No 17 0 100% 0% 10 20 33% 67% 0.008* RFA liver - Yes - No 17 0 100% 0% 24 6 20% 80% 0.074* Postoperative complications a - Yes - No 17 0 100% 0% 24 6 20% 80% 0.074* Radicality - R0 - R1 - R2 - Tumor spill 17 0 0 0 100% 0% 0% 0% 24 1 2 4 80% 3% 7% 13% b 0.048**
RFA: Radiofrequency ablation R0: Microscopically radical resection R1: Microscopically irradical resection R2: Macroscopically irradical resection
a Postoperative complications were graded according to the five-point scale as
proposed by Dindo and Clavien12. Grade 1 complications were not recorded. b Percentages exceed 100% because one patient had an R1 resection and tumor spill.
* Fisher’s exact test
Figure 3. Disease specific survival after surgery for gastric GIST according to radicality of the resection
R0: Microscopically radical resection R1: Microscopically irradical resection R2: Macroscopically irradical resection
of intra-operative tumour spill, although other factors contributing to tumour rupture (e.g. necrosis) should be acknowledged. All patients who died of disease recurrence had either an irradical resection or intra-operative tumour spill, despite adjuvant imatinib treatment. This underlines the importance of radical surgical resection without tumour spill, even in the era of imatinib treatment.
Imatinib treatment followed by surgery in metastatic disease has been investigated in patients with GISTs at all sites.6, 8-9, 21-24 Survival rates in responsive or stable disease
compare favourable to those in patients with progressive disease. In three studies, postoperative survival rates in patients with progressive disease were reported and were significantly worse than those in patients with responsive disease.6, 9, 23, 25 This is
in line with our findings and the role of surgery in patients with progressive disease on preoperative imatinib treatment can be doubted.
Surgery can complement targeted therapy by resecting vital tumour cells that have acquired resistance against the targeting compound. One mechanism of acquired resistance to imatinib is through the development of secondary mutations. For example,
Figure 4. Timeline of 30 patients treated with preoperative imatinib for gastric GIST grouped according to the radiological response* prior to surgical resection
* Radiologic response according to Choi criteria11
# Patient with metastatic disease
† Patient who died of recurrent GIST during follow-up T0 date of surgery
a KIT exon 13 V654A mutation has been associated with imatinib resistance.26 This
mutation was found in the resection specimen of one of our patients who had been operated for radiologic stable disease after an initial good response to imatinib (data not shown). After 8 months of follow-up, this patient exhibits no signs of tumour recurrence.
CONCLUDING REMARKS
In the present study, only patients with gastric GISTs were included. In previous papers, the surgical treatment of GISTs has been studied primarily in patient series with GISTs at various sites, thus reporting varying surgical procedures and varying survival data. Our study describes a large series of patients who were operated for gastric GIST with or without preoperative imatinib. It was found that primary surgical resection small GISTs confined to the stomach offers an excellent prognosis. In case of locally advanced disease, surgical resection should be performed preferably after preoperative imatinib treatment and seems most beneficial in responsive or stable disease. Similarly, in patients with metastatic disease in whom the disease is progressive on imatinib treatment, the role of surgical resection is doubtful. Irrespective of the initial response to preoperative treatment, an irradical resection or intra-operative tumour spill is associated with a poor prognosis and should thus be avoided. Patients with progressive disease on preoperative imatinib, should be considered for second line or experimental drug treatment.
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