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Abstract

Objective:

To determine prognostic factors associated with survival in patients with surgically managed gastrointestinal stromal tumours (GISTs).

Methods:

This retrospective study included 374 patients with pathologically confirmed GISTs. Medical records were reviewed and prognostic factors associated with adverse outcomes were determined.

Results:

A total of 337 patients underwent complete resection with curative intent; 37 underwent incomplete resection. Overall mean survival time was 127.3 months; 5-year survival rate was 70.4%. Multivariate analyses determined that tumour size, risk status (of recurrence or metastasis) and surgical procedure were significant predictive factors for survival. There was a significant difference in the 5-year survival rate between patients who received adjuvant imatinib compared with those who did not (75.1% versus 13.8%).

Conclusions:

Patients with GISTs managed by surgical resection combined with targeted chemotherapy had a good prognosis. Clinical factors predictive of survival included tumour size, risk status and surgical procedure.

Keywords

Gastrointestinal stromal tumour Outcome Prognostic factors Survival

Introduction

Gastrointestinal (GI) stromal tumours (GISTs) are a rare but distinct histopathological group of intestinal neoplasms of mesenchymal origin, first described in 1983.^1,2 The origin of GISTs has been identified as the interstitial cells of Cajal, which are pluripotent intestinal pacemaker cells.³ Further delineation of the cellular characteristics of GISTs has come from the identification of CD117 and CD34 expression in the majority of these neoplasms.^4–6 The stomach is the most common site of GISTs, although they can occur throughout the GI tract.^7–9 Prognostic indicators include tumour size, mitotic count and tumour location^5,10 as well as mutations in the receptor tyrosine kinase KIT gene, which have been identified in 80 – 85% of GISTs.^11–13 Up to 90% of GISTs contain mutations in either KIT or the platelet-derived growth factor receptor-α gene, but the presence or absence of a mutation does not by itself identify a GIST as benign or malignant.^14–17 The overall prognosis of GISTs has improved dramatically since the introduction of kinase-inhibitor therapies, such as imatinib, but surgical resection remains the primary treatment.¹⁸ GISTs have a high rate of recurrence and metastasis,¹⁸ and distinguishing high-risk patients from those at low risk of recurrence and metastasis may help to reduce the economic burden of the disease and limit the side-effects of unnecessary adjuvant chemotherapy.

The aim of this retrospective study was to determine the prognostic factors associated with survival in a cohort of surgically managed patients with pathologically confirmed GISTs.

Patients and methods

Study Population

This retrospective study included all patients who had undergone surgical treatment for GISTs (complete or palliative resection, or exploratory surgery with biopsy) and were enrolled in the database of the Sun Yat-Sen University Cancer Centre, Guangzhou, Guangdong, China, between January 1990 and December 2009.

All patients included in the study provided written informed consent. The study did not require ethics committee approval because of its retrospective design, and all patients received standard treatment.

Pathological Findings

Tumour tissue sections obtained from the medical records of each patient were reviewed by two independent pathologists. Mitotic index was determined in 50 high-power fields (× 400 magnification) of haematoxylin and eosin-stained tissue sections.

Data Collection

The medical records of all study subjects were examined and data regarding age, gender, tumour location and diameter, histological grade, stage (according to American Joint Committee on Cancer [AJCC] guidelines¹⁹), presence of cystic change, preoperative disseminated metastasis, cell type (spindle, epithelial or mixed type), surgical treatment type (complete, partial or extended resection), metastasis risk (according to criteria established by Fletcher²⁰ and Miettinen²¹) and use of imatinib chemotherapy (neoadjuvant, adjuvant or palliative) were collected.

Follow-Up

Patients were followed-up for survival. Follow-up began in January 2003 and annual updates were provided throughout the study period (by telephone or letter) until 28 February 2010.

Statistical Analyses

The χ²-test was used to analyse the relationships between risk factors and overall survival rate. Kaplan–Meier survival analysis, univariate analysis, log-rank test and Cox regression analysis were used to determine the effects of risk factors on prognosis. Statistical analyses were performed using SPSS^® statistical software, version 16.0 (SPSS Inc., Chicago, IL, USA) for Windows^®. A P-value < 0.05 was considered to be statistically significant.

Results

This retrospective analysis included 374 Chinese patients with GIST (233 [62.3%] males, 141 [37.7%] females; median age 55 years [range 19 – 81 years]), identified from a total of 13 790 patients enrolled on the database. Median tumour diameter was 7.0 cm (range 0.4 – 45.0 cm). Demographic and clinical characteristics, and details of surgical treatments, are shown in Table 1. A total of eight cases were lost to follow-up (follow-up rate 97.9%). The median duration of follow-up was 36.5 months (range 5 – 86 months); 263 cases were followed up for > 2 years.

Data regarding tumour staging according to AJCC criteria¹⁹ are shown in Table 2. A significantly higher proportion of tumours located in the stomach were at an early stage of disease (stages I and II) compared with tumours located in other regions of the GI tract (56.3% versus 30.4%, P < 0.001).

TABLE 1:

Demographic, clinical and surgical characteristics of Chinese patients with gastrointestinal stromal tumours (GISTs) included in the present study to identify GIST prognostic factors, stratified according to gender

Characteristic	Males n = 233	Females n = 141	Total n = 374
Age, years	56.0 (19 – 81)	54.5 (26 – 81)	55.0 (19 – 81)
Primary tumour location
Stomach	117 (50.2)	69 (48.9)	186 (49.7)
Duodenum	12 (5.2)	5 (3.5)	17 (4.5)
Small intestine	66 (28.3)	43 (30.5)	109 (29.1)
Colorectum	36 (15.5)	22 (15.6)	58 (15.5)
Colon	NA	NA	18 (4.8)
Rectum and anal canal	NA	NA	40 (10.7)
Oesophagus	2 (0.9)	2 (1.4)	4 (1.1)
Tumour diameter
< 2 cm	42 (18.0)	16 (11.3)	58 (15.5)
2 – 5 cm	50 (21.5)	31 (22.0)	81 (21.7)
5 – 10 cm	77 (33.0)	45 (31.9)	122 (32.6)
> 10 cm	64 (27.5)	49 (34.8)	113 (30.2)
Mitotic count^a
≤ 5	109 (46.8)	59 (41.8)	168 (44.9)
> 5	124 (53.2)	82 (58.2)	206 (55.1)
Complete resection	207 (88.8)	130 (92.2)	337 (90.1)
Tumour removal^b	69 (29.6)	49 (34.8)	118 (31.6)
Whole organ removal^c	51 (21.9)	38 (27.0)	89 (23.8)
Extended resection^d	87 (37.3)	43 (30.5)	130 (34.8)
Incomplete resection	26 (11.2)	11 (7.8)	37 (9.9)
Palliative resection	NA	NA	28 (7.5)
Exploratory surgery with biopsy	NA	NA	9 (2.4)

Data presented as n (%) of patients or median (range).

Mitotic count/50 high-power microscope fields (× 400 magnification).

Tumour removal with margins < 2 cm.

Tumour removal with margins ≤ 2 cm, lymph node dissection and other combined organ resection.

Lymph node dissection and combined organ resection including liver resection, distal pancreatectomy, splenectomy, nephrectomy and oophorectomy.

NA, data not available.

No statistically significant between-gender differences (P ≤ 0.05); χ²-test.

TABLE 2:

Tumour staging in Chinese patients with surgically managed gastrointestinal stromal tumours (n = 374) and a subgroup of patients who underwent complete tumour resection (n = 337), stratified according to tumour location

	All patients		Complete tumour resection
Stage^a	Stomach and oesophagus	Other locations	Stomach and oesophagus	Other locations
I	79 (41.6)	27 (14.7)^***	79 (44.1)	27 (17.1)^***
IA	68 (35.8)	NA	68 (40.0)	NA
IB	11 (5.8)	NA	11 (6.1)	NA
II	28 (14.7)	29 (15.8)	27 (15.1)	27 (17.1)
III	68 (35.8)	96 (52.2)^**	66 (36.9)	89 (56.3)^***
IIIA	16 (8.4)	6 (3.3)^*	15 (8.4)	6 (3.4)
IIIB	52 (27.4)	90 (48.9)^***	51 (28.5)	83 (52.5)^***
IV	15 (7.9)	32 (17.4)^**	7 (3.9)	15 (9.5)^*
Total	190 (100)	184 (100)	179 (100)	158 (100)

Data presented as n (%) of patients.

American Joint Committee on Cancer staging system.¹⁹

NA, data not available.

P < 0.05,

P < 0.01,

***

P < 0.001 versus tumours located in the stomach; χ²-test.

The mean survival time in the total patient population was 127.3 months (median 150.0 months) (Fig. 1). When survival rates were stratified according to the location of the primary tumour, patients with tumours located in the small intestine had a significantly lower 5-year survival rate than patients with tumours in the stomach or colorectum (P < 0.05, Table 3).

FIGURE 1:

Kaplan–Meier survival analysis of all the surgically managed Chinese patients with gastrointestinal stromal tumours who were followed up (n = 366). Mean and median survival times were 127.3 months and 150.0 months, respectively

TABLE 3:

Survival rates in surgically managed Chinese patients with primary tumours of the stomach, small intestine and colorectum (n = 362)

		Survival rate, %
Primary site	n	1 year	2 years	3 years	4 years	5 years
Stomach	182	98.4	90.8	NA	80.9	75.6
Small intestine and duodenum	124	97.6	87.5	78.6	73.7	59.5^*
Colorectum	56	100	94.4	78.4	NA	75.3
Total	362	98.4	90.3	83.2	78.3	70.4

NA, data not available.

P < 0.05 compared with 5-year survival in all other groups; χ²-test.

The 1-, 2-, 3-, 4- and 5-year survival rates for patients who underwent complete or incomplete resection are shown in Table 4. The mean duration of survival was significantly longer in patients who underwent complete resection (n = 337; 152.0 ± 52.9 months) compared with those who underwent incomplete resection (n = 37; 43.0 ± 13.8 months; P < 0.001). Patients who underwent incomplete resection and subsequently received imatinib chemo therapy (n = 28) had a significantly better 5-year survival rate than those who underwent incomplete resection but received no chemotherapy (41.9% versus 0.0%; P = 0.018). Median survival in the nine patients with incomplete resection who did not receive imatinib was 16 months (range 8 – 21 months).

TABLE 4:

Survival rates in Chinese patients with gastrointestinal stromal tumours (n = 366), stratified according to complete or incomplete tumour resection and use of imatinib chemotherapy

		Survival rate, %
Group	n	1 year	2 years	3 years	4 years	5 years
Complete resection	331	99.7	93.8	86.8	82.0	73.4
Incomplete resection, total	35	86.5	59.3	51.4	46.7	33.1^***
With imatinib chemotherapy	28	96.4	79.9	69.1	62.8	41.9
Without imatinib chemotherapy	7	NA	0.0	0.0	0.0	0.0^*

NA, data not available.

***

P < 0.001 versus 5-year survival in complete resection group

P < 0.05 versus 5-year survival in incomplete resection with imatinib chemotherapy group; χ²-test.

Survival data stratified according to the use of imatinib chemotherapy are given in Table 5. Patients who received adjuvant imatinib had higher 5-year survival rates than those who received no imatinib chemotherapy (75.1% versus 13.8%, respectively, P < 0.001).

TABLE 5:

Survival rates in Chinese patients with gastrointestinal stromal tumours (n = 366), stratified according to the use of imatinib chemotherapy

Imatinib chemotherapy	n	Duration of treatment, months, median (range)	Survival rate, %
Imatinib chemotherapy	n	Duration of treatment, months, median (range)	1 year	2 years	3 years	4 years	5 years
Neoadjuvant	8	6 (1 – 11)	100	100	100	100	100
Adjuvant	75	12.5 (1 – 56)	100	98.4	95.0	75.1	75.1
Palliative	105	20 (1 – 84)	92.0	83.0	76.0	72.0	66.0
None	178	–	97.0	65.8	47.0	34.4	13.8^***

***

P < 0.001 versus 5-year survival in adjuvant imatinib group; χ²-test.

Univariate analysis revealed that the factors predictive of improved survival were: complete resection (P = 0.042); primary tumour location (gastric tumours associated with improved survival; P = 0.037); epithelial/ spindle cell type (P = 0.005); absence of surrounding tissue invasion (P = 0.027); absence of cystic change (P < 0.001); low mitotic count (less than five; P < 0.001); small tumour diameter (P < 0.001); early stage (P < 0.001); low potential malignant risk (P = 0.001); and extended resection (P = 0.001). Gender, age, bleeding, necrosis, preoperative disseminated metastasis and imatinib treatment were not found to be predictive of survival.

Multivariate analysis determined that tumour size (P = 0.017), high risk of recurrence or metastasis (P = 0.040), and surgical procedure (complete or partial resection; P = 0.044) were all significant prognostic factors. The use of imatinib chemotherapy was not included in this analysis.

Discussion

The incidence of GISTs is approximately 10 – 15 cases/million people per year and is most common in men and patients aged 55 – 65 years.²² A study performed at the New York Memorial Sloan-Kettering Cancer Centre reported 200 cases of GISTs (accounting for 5.7% of all sarcoma patients) with a median age of 58 years.¹⁰ The database used in the present study included 13 790 patients with GI cancer. The demographic and clinical characteristics of the 374 patients who were diagnosed with GISTs, included in the current cohort, were consistent with previously published data.^7–9

All parts of the GI tract can be affected by GISTs. The most common site is the stomach (39 – 65% of all GI cancers), followed by the small intestine (21 – 43%), colon and rectum (15 – 20%) and oesophagus (approximately 5%).^7–9 The majority of GISTs in the present study were found in the stomach, followed by the small intestine, rectum and anal canal, colon, duodenum and oesophagus; this distribution is similar to other reports.^22–24 The clinical staging of GISTs in the present analysis was also consistent with the literature,²² with more tumours of the stomach found to be at an earlier stage than those located elsewhere. Patients in the present cohort had a 5-year survival rate of 73.4% after complete resection, but the site of the primary tumour can have an influence on disease prognosis. The prognosis of gastric GISTs is better than that for GISTs in other locations, with a reported 5-year survival rate of between 76.5% and 86.0%.⁷ These survival rates were higher than those observed in patients with colorectal or small intestinal GISTs in the present study, which is consistent with other literature.⁷

Prior to the introduction of targeted drug therapy, such as imatinib, the 5-year survival rate for surgically treated GISTs was approximately 50%,^10,25 with a median disease-free survival of 18 months and 60% of recurrences observed within 2 years of surgery.²⁶ Tyrosine kinase inhibitors, such as imatinib, have improved disease-free survival.¹⁸ The best treatment modality for GIST is considered to be surgical resection combined with molecular targeted therapy, with approximately 85% of patients with GISTs undergoing complete resection.²⁷ Over 90% of patients in the present study underwent complete tumour removal and the 5-year survival rate of these patients was significantly higher than for those who underwent incomplete resection. Some patients who underwent incomplete resection did so because their tumours were more advanced, which may be the reason for the lower 5-year survival rate in this group.

Approximately 50% of patients with GISTs experience local relapse, even after R₀ resection.²⁸ There is no standard definition for R₀ resection but a margin of 2 cm was considered sufficient in the present study. Another study reported a recurrence rate of 36% after R₀ GIST resection.²⁹

Numerous prognostic factors were investigated in the present analysis. Univariate analysis determined that type of surgical procedure, primary tumour site, cell type, metastasis, cystic changes, mitotic count, tumour diameter and staging, malignant risk assessment and multiorgan resection all significantly influenced survival. Tumour size, high-risk status and surgical procedure were significant factors for survival when a multivariate analysis was adopted (the use of chemotherapy was not included in this analysis). In contrast to other findings,³⁰ tumour location, patient age or gender and the presence of bleeding, necrosis or preoperative disseminated metastasis were not significant predictors of survival in this study.

The present retrospective analysis determined that surgical resection was the primary treatment for adults with GISTs in the study centre, despite the availability of targeted drug therapy. Patients receiving imatinib chemotherapy had a better overall survival rate than those who did not receive imitanib. Identification of those patients with GISTs who are at high risk of recurrence may limit the economic burden of the disease and reduce the unnecessary use of adjuvant chemotherapy. Tumour size, high-risk status and surgical procedure were significantly predictive of survival in patients with GISTs.

Footnotes

The authors had no conflicts of interest to declare in relation to this article.

Acknowledgements

We thank Dr Fu-Long Wang, Dr Zhi-Heng Peng and Dr Wen-Hua Fan for collection of the clinical data.

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Prognostic Factors in Surgically Managed Gastrointestinal Stromal Tumours

Abstract

Objective:

Methods:

Results:

Conclusions:

Keywords

Introduction

Patients and methods

Study Population

Pathological Findings

Data Collection

Follow-Up

Statistical Analyses

Results

Discussion

Footnotes

Acknowledgements

References