|Ahead of print publication
Demographic and clinicopathological profile of patients of gastrointestinal stromal tumor from a tertiary care center of North India: An observational study
Mayank Aggarwal1, Archana Aggarwal2, Savita Arora1, Arun Kumar Rathi1, Kishore Singh1
1 Department of Radiation Oncology, Maulana Azad Medical College and Lok Nayak Hospital, New Delhi, India
2 Department of Radiation Oncology, Rajiv Gandhi Cancer Institute and Research Center, New Delhi, India
Department of Radiation Oncology, Maulana Azad Medical College and Lok Nayak Hospital, New Delhi - 110 002
Source of Support: None, Conflict of Interest: None
Background: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal system. This study was aimed to analyze the demographic and clinicopathological data of the patient with a primary diagnosis of GIST, who were treated at our center.
Materials and Methodology: Patients of GIST registered at our center from September 1, 2008, to August 31, 2016, were enrolled for this study. Patient's demographic and clinicopathological data were collected from clinical records. The data were represented as absolute number, percentage, and median (range: minimum to maximum), whichever applicable.
Results and Observations: The analysis of 27 patients revealed that pain was the most common clinical feature. The stomach was the most common primary site. Most of the patients underwent upfront radical surgery (92.6%) followed by adjuvant imatinib. Histopathological data revealed that most tumors were >10 cm in size, 51.8% of patients had low mitotic index, and all these patients were either immunohistochemical positive for cluster differentiation 117 or KIT. The median duration of tyrosine kinase inhibitors therapy (imatinib) in our study individual was 2.5 years with a range of 4.8 months–3 years. Response assessment revealed 74.1% complete remission, 11.1% stable disease, and 3.7% progressive disease. Median overall survival in study individuals was 2.63 years (range: 0.1–8.6 years). Patient- and tumor-related factors were analyzed for prognostic significance using univariate survival analysis; however, none was found to have a significant prognostic correlation.
Conclusions: Patients who underwent upfront surgery followed by adjuvant imatinib has shown good response to the treatment. However, the limitation of the small sample size and short follow-up in this study may not be a true data representation of the entire population
Keywords: Clinical, demography, gastrointestinal stromal tumor, India, pathological, profile
|How to cite this URL:|
Aggarwal M, Aggarwal A, Arora S, Rathi AK, Singh K. Demographic and clinicopathological profile of patients of gastrointestinal stromal tumor from a tertiary care center of North India: An observational study. J Can Res Ther [Epub ahead of print] [cited 2019 Nov 21]. Available from: http://www.cancerjournal.net/preprintarticle.asp?id=269746
| > Introduction|| |
Gastrointestinal stromal tumor (GIST) is an uncommon visceral sarcoma. It is the most common soft-tissue sarcoma of the gastrointestinal (GI) tract with stomach (60%) and small intestine (30%) being the most common primary GI sites. This study was aimed to analyze the demographic, clinicopathological data of the patient with primary diagnosis of GIST, who were treated at the Department of Radiotherapy and Oncology at Maulana Azad Medical College and Lok Nayak Hospital, New Delhi, India.
| > Materials and Methodology|| |
Patients of GIST, who were registered at the Department of Radiotherapy and Oncology at Maulana Azad Medical College and Lok Nayak Hospital from September 1, 2008, to August 31, 2016, were enrolled for this study. Further follow-up data of these patients were reviewed till March 31, 2017.
Patients who were included in this study were those who had histologically proven GIST, chemotherapy naïve at the time of presentation, eastern cooperative oncology group performance status of 0, 1, or 2. Patients with refractory or relapsed disease status at the time of presentation and who had a history of chemotherapy/radiotherapy were excluded from this study.
Structured data included information about patient's demographic data, clinical presentation, appropriate therapeutic intervention, and posttherapeutic response (response evaluation criteria in solid tumors, version 1.1). The data were represented as absolute number, percentage, and median (range: minimum to maximum), whichever applicable. The median value was calculated by Microsoft excel formula (MEDIAN). Kaplan–Meier curve was generated using SPSS Statistics for Windows, Version 17.0. Chicago: SPSS Inc.
| > Results and Observations|| |
In the said period, a total of 27 patients of GIST were registered at our institution. After analysis of their clinicopathological and demographic profile, the data were compiled in number, percentage of patients, and the median value (with range), whichever applicable.
Of 27 patients, there were 17 males and 10 females with male: female ratio of 1.7:1. The median age of the study group was 53 years with a range of 11–68 years of age. There were a total of 13 vegetarian and 14 nonvegetarian individuals. Among the study participants, only three patients had a history of alcohol intake, six patients were smokers, and six patients had a history of tobacco chewing. There was no cancer-related death or death from a similar illness in the family of any of these individuals.
After analysis of data, the pain was found to be the most common clinical feature among the patients of GIST. Lump and bleeding were the second and third most common clinical feature, respectively. The incidence of all the clinical features has been shown in [Table 1]. Gastric GIST was the most common site of the disease presentation, followed by small intestine (jejunum more than duodenum). The number and percentage of site-specific presentation have been shown in [Table 1]. After data analysis, it was realized that most of these patients presented at the early resectable stage. In fact, out of six patients who presented with metastatic disease, four patients underwent upfront radical resection along with complete metastasectomy [Table 1].
|Table 1: Demographic and clinicopathological profile of the study population|
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Of 27 patients, 24 patients underwent upfront surgery, two patients received neoadjuvant tyrosine kinase therapy with imatinib, whereas one patient did not turn up for treatment after initial diagnosis. Of two patients who received neoadjuvant treatment one patient of rectal GIST showed partial response and was further taken for abdominoperineal resection with curative intent. Other patient had gastric GIST, but the tumor progressed after neoadjuvant imatinib therapy. This patient was further switched to sunitinib.
Histopathological data revealed that most of the patients presented with the size of primary disease of more than 10 cm [Table 1]. Fourteen patients have mitotic count of <5/50 high-power field (HPF) while thirteen patients had this value of more than 5/50 HPF. All these patients were either immunohistochemical (IHC) positive for cluster differentiation (CD) 117 or KIT. Other IHC markers are listed in [Table 1].
Of 24 patients who underwent curative surgery, 24 received adjuvant imatinib while one patient did not turn up for the adjuvant therapy. The median duration of tyrosine kinase therapy in our study individual was 2.5 years with a range of 4.8 months–3 years, [Table 1]. Response assessment revealed 74.1% complete remission, 11.1% stable disease, and 3.7% progressive disease. Response assessment data of three patients was not available at the time of data evaluation. At the time of data analysis, 19 patients are still alive, two died of disease and status of four patients are not known because of lost to follow-up. The median duration of overall survival (OS) in study individuals was 2.63 years (range: 0.1–8.6 years) [Figure 1].
|Figure 1: Kaplan–Meier graph for overall survival with survival probability; (Group A represents the study population)|
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Patient- and tumor-related factors were analyzed for prognostic significance using univariate survival analysis; however, none was found to have a significant prognostic correlation.
| > Discussion|| |
The precise cellular origin of GIST has been proposed to be the interstitial cell of Cajal, an intestinal pacemaker cell. On ultrastructural examination, the Cajal cell has characteristics of both smooth muscle and neural differentiation. Thus, neoplastic Cajal cells could preferentially express one, both, or neither of these features, accounting for the variants of GIST. Activating mutations most commonly associated with GIST are KIT receptor tyrosine kinase (80%), or platelet-derived growth factor receptor alpha (PDGFRA) tyrosine kinase.,
Patients of GIST may present with a variety of sign and symptoms including early satiety, abdominal pain or swelling, hemorrhage/bleeding, anemia, and GI obstruction. Liver metastases and/or abdominal cavity metastases may also be observed. However, lymph node metastases and extra-abdominal metastases are rare. In our study, the pain was found to be the most common clinical feature followed by lump/swelling and bleeding. Gastric GIST was the most common site of the disease presentation, followed by small intestine (jejunum more than duodenum).
In comparison with other Indian studies, the median age of diagnosis was found to be 56 years by Adyar and Kidwai group and 45.5 years in AIIMS group. However, this figure was 53 years in the present study. Unlike AIIMS group with small intestine as the most common site of primary origin, the stomach was found to be the most common site in Adyar and Kidwai study, finding similar to the present study. In the present study, most of the patients presented in resectable stage, while in AIIMS study, majority (99%) comprised of either unresectable or metastatic stage.
GISTs are usually frail tumors. Biopsy is usually required to confirm the diagnosis and assessment of the mitotic rate that is expressed as the number of mitoses in 50 HPF (equivalent to 5 mm2 of tissue). Genetic testing to identify KIT and/or PDGFRA mutations and IHC staining for CD117, discovered on GIST (DOG)-1, and/or CD-34 are cornerstones in the diagnosis of GIST. KIT exon 9 mutations are commonly seen in intestinal GISTs and PDGFRA exon 18 mutations in gastric GISTs. About 10%–15% of GISTs have no detectable KIT or PDGFRA mutations (wild-type GIST). CD 117 is the most commonly expressed IHC marker (95%) in GIST. Other markers include CD34 antigen (70%), smooth muscle actin (25%), and desmin (<5%). DOG1 is a calcium-dependent, receptor-activated chloride channel protein and it is expressed in GISTs independent of mutation type. DOG1 is a useful IHC marker for CD117/KIT/PDGFRA-negative GIST. Therefore, DOG1 and KIT are used together in doubtful cases exhibiting unexpected KIT negativity or positivity. In our study group, 51.8% of patients had mitotic rate of <5/50 HPF, and all patients were either IHC positive for CD117/KIT. Mutation analysis was however not done in any case due to the limitation of institutional infrastructure.
Most commonly used factors for the risk stratification of GIST include tumor size, mitotic rate, and tumor site. Factors that are associated with poor disease-free survival include KIT exon 9 duplication, KIT exon 11 deletions, nongastric site, larger tumor size, and high mitotic index, whereas PDGFRA exon 18 mutations are associated with better prognosis. Female sex is an independent prognostic factor for higher progression-free survival (PFS) and OS in patients treated with standard-dose imatinib. In our study group, 48.1% of patients had nongastric GIST, 55.6% of patients had tumor size of more than 10 cm, 48.1% of patients had high mitotic index, and 37% of patients were female. However, no recurrence or residual disease has been noted postsurgery, within a median OS period of 2.63 years (range: 0.1–8.6 years).
GISTs are generally resistant to conventional chemotherapies. Since KIT activation is a part of pathogenesis in GISTs, KIT inhibition has a promising role in the primary treatment of GIST. Imatinib is a selective inhibitor of the KIT protein tyrosine kinase, has produced durable clinical benefit and objective responses in most patients with GIST. As mentioned earlier, imatinib may be used in a neoadjuvant setting in initially unresectable of locally advanced disease. However, the decision of its use should be made on an individual basis.
Surgery is the primary treatment of choice for patients with localized or potentially resectable GIST lesions. Lymphadenectomy is usually not required given the low incidences of nodal metastases. Most of our study group patients (74.1%) presented at the early resectable stage. In fact, out of six patients who presented with metastatic disease, four patients underwent radical resection along with complete metastasectomy. Therefore, 88.9% of patients underwent upfront surgery with curative intent.
Patients with locally advanced or unresectable disease may have a favorable outcome with neoadjuvant tyrosine kinase inhibitor (TKI) therapy with imatinib. In our study group, only two patients received neoadjuvant TKI therapy, good response was seen only in one out of these two patients. However, with small number of patient in this group, a definitive conclusion cannot be reached. If persistent metastatic or residual tumor remains after surgery, then imatinib should be continued as soon as the patient is able to tolerate oral intake. In 85% of patients, complete resection is possible, but approximately 50% of these patients will develop local recurrence or metastasis; and therefore, 5-year survival rate is only about 54%. Median time to recurrence is about 2 years after resection of high-risk GIST. Therefore, it has been suggested that at least 3 years of adjuvant treatment results in higher relapse-free survival (RFS) for patients with high-risk disease. A Phase III, double-blind study (ACOSOG Z9001) revealed higher RFS with no OS benefit with postoperative imatinib 400 mg, given for a total of 1 year for primary localized GISTs (3 cm or greater in size). Another randomized Phase III study from the Scandinavian Sarcoma Group XVIII/AIO suggest that postoperative imatinib administered for 36 months improves RFS and OS compared to 12 months for patients with a high estimated risk of recurrence after surgery.
In our study group, 96% of patients who underwent curative surgery, received adjuvant TKI therapy with oral imatinib 400 mg. The median duration of adjuvant TKI was 2.5 years, with 51.9% of patients were still on planned 3 years of adjuvant TKI therapy. Response assessment revealed 74.1% complete remission, 11.1% stable disease, and 3.7% progressive disease.
Clinical progression developing during the first 6 months of imatinib therapy can be termed as primary imatinib resistance, while patients progressing on imatinib after 6 months of therapy with an initial response or disease stabilization are known to have secondary imatinib resistance. KIT exon 9 mutations, PDGFRA exon 18 D842V mutations, or succinate dehydrogenase deficient GISTs are known factors for primary imatinib resistance., Dose escalation to 800 mg/d or switching to sunitinib is a reasonable option for patients progressing on imatinib 400 mg/day.,,
KIT or PDGFRA mutation has been recognized as predictive factors for response to imatinib therapy. Better response rates, PFS, and OS can be predicted with the presence of KIT exon 11 mutations as compared to KIT exon 9 mutations or wild-type GIST, as shown in BFR14 trial 320 and US-Finnish B2222 Phase II study. The presence of KIT exon 11 mutations can reduce the risk of death by more than 95%.
A meta-analysis of EORTC 62005 and SWOG S0033/CALGB 150105 Phase III trials showed that in the presence of KIT exon 9 mutations, treatment with high-dose imatinib (800 mg/d) resulted in a significantly improved PFS. Heinrich et al. reported that sunitinib-induced higher response rates in patients with primary KIT exon 9 mutations than those with KIT exon 11 mutations (58% vs. 34%, respectively).
Regorafenib is a multikinase inhibitor with activity against KIT, PDGFR, and VEGFR have been approved for the treatment of GIST after failure of imatinib and sunitinib therapy. It has shown improvement in PFS and disease control rate. Other agents that have been approved in GIST resistant to imatinib and sunitinib are sorafenib, nilotinib, dasatinib, and pazopanib. Everolimus in combination with a TKI (i.e., imatinib, sunitinib, and regorafenib) may also be active in imatinib-resistant GIST., The clinical benefit of nilotinib may be specific for patients harboring KIT exon 17 mutations, resistant to imatinib and sunitinib. Dasatinib has demonstrated activity against PDGFRA D842V mutation, which confers the highest resistance to imatinib, and it could be an effective treatment option for this group of patients with imatinib-resistant GIST.
| > Conclusions|| |
GIST is the most common mesenchymal tumor of GI system. Surgery is the primary treatment of choice for patients with localized or potentially resectable GIST. The use of imatinib has been approved in neoadjuvant as well as adjuvant treatment of GIST. In our study group, patients who underwent upfront surgery followed by adjuvant imatinib has shown good response to the treatment with median OS of 2.65 years. However, the limitation of the small sample size and short follow-up in this study may not be a true data representation of the entire population.
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