International guidelines for GIST management^-www.drkeyurbhatt.in*

ESMO (European Society of Medical Oncologists) and NCCN (National Comprehensive Cancer Network) recommend:

1. Available data confi rm the safety and effi cacy of Imatinib mesylate at 400 mg per day as the initial standard dose to achieve response induction.
2. Data have been provided that patients with exon 9 KIT mutations fare better in terms of progression-free survival on a higher dose level i.e. 800 mg daily, which is therefore standard treatment in this subgroup.
3. Th e standard approach in the case of tumour progression is to increase the Imatinib mesylate dose to 800 mg daily. Also patient non-compliance should be ruled out as a possible cause of tumour progression, as well as drug interactions with concomitant medications.
4. Treatment should be continued indefi nitely, since treatment interruption is generally followed by relatively rapid tumour progression in virtually all cases.

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Emergence of Imatinib (Glivec) Resistance^-www.drkeyurbhatt.in*

J Gastrointest Surg (2010) 14:557–561

Abstract
Introduction Gastrointestinal stromal tumors (GISTs) are the most common gastrointestinal mesenchymal tumors. The activating mutation in the KIT (c-kit; CD117) proto-oncogene with subsequent tyrosine kinase activation plays a central role in the pathogenesis of GIST. Tyrosine kinase inhibitors are an integral part of GIST therapy. Initial response to neoadjuvant imatinib can be expected in up to 70% of the patients, thus offering an opportunity to surgically treat those with locally advanced primary or recurrent GIST. This favorable response to imatinib, however, is plagued with development of secondary resistance during the course of therapy. .
Discussion Continued monitoring by a multidisciplinary team, including a surgeon, is vital for the success of neoadjuvant imatinib therapy for unresectable primary or recurrent GIST in the context of emergence of secondary resistance. As such, surgeons should participate in managing imatinib-treated GIST, as resection may become a viable curative option.  major oncologic resections can be safely performed in older persons when their performance status and comorbidities are carefully considered.

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Surgically Managed Gastrointestinal Stromal Tumors: A Comparative and Prognostic Analysis^-www.drkeyurbhatt.in*

Presented in part at the annual meeting of the Society of Surgical Oncology, April 2007, Washington, DC.

Annals of Surgical Oncology 15(1):52–59

Background: Tyrosine kinase inhibitors have been shown to have marked clinical efficacy in patients with unresectable or metastatic gastrointestinal stromal tumors (GIST). We performed a comparative and prognostic analysis of our experience with surgically managed GIST to determine factors associated with adverse oncologic outcomes.
Methods: Oncologic outcomes of 191 patients with primary GIST surgically managed between 1978 and 2004 at a single institution were reviewed. Prognostic factors were analyzed by Cox analysis (hazard ratio [HR] and 95% confidence interval [95% CI]) and included age, sex, disease presentation (asymptomatic vs. symptomatic), tumor site (stomach, small bowel, colorectal), disease extent (localized vs. metastatic) and risk levels (high, intermediate, low, very-low) assigned on the basis of size and number of mitoses according to current National Institutes of Health recommendations. Primary end points were disease-free survival (DFS)  and disease-specific survival (DSS).
Results: A total of 186 patients (97%) had c-kit–positive GIST. There were 54% high, 22% intermediate, 18% low, and 8% very low risk GIST originating from the stomach (54%), small bowel (36%), and colon and rectum (10%). Median patient age was 65 (range, 13–91) years, and 108 subjects (57%) were male. Seventy-two percent of patients had symptomatic local disease, and 21% patients had synchronous metastases. Most (95%) underwent R0 resections of their primary tumor. Among 146 patients (76%) with localized disease at presentation undergoing R0 resection, the 5-year DFS was 65%. High-risk GIST (HR 12, 95% CI, 5–32, P < .0001), symptomatic presentation (HR 2.5, 95% CI, 1.1–6, P = .04), and GIST in the small bowel (HR 2.8, 95% CI, 1–5, P = .003) were independently associated with decreased DFS. After a median follow-up of 63 months among survivors, the 5-year DSS was 68%. High-risk disease (HR 14.3, 95% CI, 5–41, P < .0001), symptomatic presentation (HR 3.1, 95% CI, 1.2–7.9, P = .02), and GIST in the small bowel (2.6,3 95% CI, 1–5, P = .006) were independently associated with decreased DSS. Conclusions: High-risk GIST are associated with increased disease recurrence and decreased survival despite complete surgical resection. These patients should receive adjuvant therapy in the form of tyrosine kinase inhibitors

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Rectal GIST^-www.drkeyurbhatt.in*

World J Gastroenterol 2008 February 28; 14(8): 1302-1304

Rectal GISTs make up 0.1% of all tumours originating in the rectum


Since the incidence of rectal GIST is much lower than that of GIST in the stomach or small intestine,
the clinicopathological profiles of rectal GIST have not yet been accurately characterised, and there is therefore the tendency to validate the same prognostic factors for the latter as for such tumours at other sites, particularly gastric GIST.
A rate of ≤ 5 mitoses per 50 HPF is commonly used as a limit for a tumour with expected benign behaviour, and according to a large study, this can discriminate between benign and malignant tumours, especially gastric GIST.Tumours of 2 cm in diameter Transrectal ultrasound confirming a predominantly exophytic, heterogenous, hypoechoic submucosal mass (measuring 35 mm × 26 mm) on the
lateral left rectal wall. TC confirming the sonographic findings of the presence of a mass with a marked, irregular, eccentric thickening of the lateral left wall of the lower third of the rectum, but providing no evidence for either pelvic lymphadenopathy or distant metastasis. are generally expected to behave in a benign fashion.
Tumours of < 5 cm in diameter are associated with a better survival rate than those of 5 cm-10 cm in diameter, which in turn have a better prognosis than those of > 10 cm in diameter.

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Imatinib where does it stays^-www.drkeyurbhatt.in*

The role of neoadjuvant therapy of Imatinib in GIST is under evaluation by the Radiation Therapy Oncology Group (RTOG) that will correlate molecular markers with clinical response as assessed by imaging and pathological evaluation of the resected specimen. The neoadjuvant therapy will be useful in patients with large-size tumor or location of the tumor at the site where resection is associated with the risk
of severe organ dysfunction where a negative margin is difficult to achieve. The aim of such a treatment is to
downsize the tumor for a less morbid surgical procedure. In addition, the use of Imatinib neoadjuvant therapy with or without an adjuvant treatment might help in controlling micrometastatic disease. Again, the duration and dose of Imatinib in the neoadjuvant setting are yet undecided. Less than 5% patients have complete clinical response to Imatinib.


Now the first line of treatment of the recurrent or 

metastatic GIST is Imatinib. The use of Imatinib mesylate 

in recurrent or metastatic GIST in prospective trial has 

shown response in 50% patients. 

Surgical resection of the localized GIST is the mainstay therapy, as a resection of tumor renders only a chance of cure

Gastrointestinal cancers symposium, San Francisco, 2004.



Imatinib adjuvant therapy
The use of Imatinib as an adjuvant therapy after the complete resection of primary GIST is under evaluation. The American College of Surgeons Oncology Group (ACOSOG) is conducting a phase-II prospective trial on patients of GIST.

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