Indian Journal of Cancer
Home  ICS  Feedback Subscribe Top cited articles Login 
Users Online :2549
Small font sizeDefault font sizeIncrease font size
Navigate here
  Search
 
  
Resource links
 »  Similar in PUBMED
 »  Search Pubmed for
 »  Search in Google Scholar for
 »Related articles
 »  Article in PDF (290 KB)
 »  Citation Manager
 »  Access Statistics
 »  Reader Comments
 »  Email Alert *
 »  Add to My List *
* Registration required (free)  

 
  In this article
 »  Abstract
 » Introduction
 » Conclusions
 »  References
 »  Article Tables

 Article Access Statistics
    Viewed3889    
    Printed86    
    Emailed0    
    PDF Downloaded592    
    Comments [Add]    
    Cited by others 3    

Recommend this journal

 

  Table of Contents  
MINI SYMPOSIUM: STROMAL TUMOR
Year : 2013  |  Volume : 50  |  Issue : 1  |  Page : 31-40
 

Management of gastrointestinal stromal tumor: The lmatinib era and beyond


1 Indian Cooperative Oncology Network, 74 Jerbai Wadia Road, Parel East, Mumbai, India
2 Department of Medical Oncology, Tata Memorial Hospital, Mumbai, India

Date of Web Publication20-May-2013

Correspondence Address:
P M Parikh
Indian Cooperative Oncology Network, 74 Jerbai Wadia Road, Parel East, Mumbai
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.112289

Rights and Permissions

 » Abstract 

The availability of imatinib followed by other tyrosine kinase inhibitors (TKIs) has dramatically altered the outcome of gastrointestinal stromal tumor (GIST). Patients with advanced or poor risk disease can now expect survival measured in years instead of months. An experienced multi disciplinary team (MDT) will be able to personalize therapy to ensure maximum benefit. This review will provide the updated information and finer points regarding state of the art management of GIST with the use of imatinib and other TKIs.


Keywords: Consensus, guidelines, multidisciplinary, sarcoma, targeted therapy, tyrosine kinase inhibitor


How to cite this article:
Parikh P M, Gupta S. Management of gastrointestinal stromal tumor: The lmatinib era and beyond. Indian J Cancer 2013;50:31-40

How to cite this URL:
Parikh P M, Gupta S. Management of gastrointestinal stromal tumor: The lmatinib era and beyond. Indian J Cancer [serial online] 2013 [cited 2020 May 29];50:31-40. Available from: http://www.indianjcancer.com/text.asp?2013/50/1/31/112289



 » Introduction Top


Although sarcomas constitute less than 1% of all the cancers globally, they form an attractive theme for oncology research. This is because understanding their natural history, signaling pathways and pathogenesis offers a wealth of insight about potential targets for new therapeutic approaches in a disease that is generally considered incurable in the metastatic stage. However, there are continuing challenges in researching and managing this disease. Because the disease affects only a small number of patients, there is less incentive for pharmaceutical companies to commit funding for new drug development even with the incentives of orphan drug status. Biologically the disease is considerably heterogeneous, with a spectrum of genetic profiles that can test the strength and rationale of even the best clinical trial design. It is like opening the Pandora's Box when one tries to unravel the multiple circuits and initiators of signaling pathways involved in sacromas. [1]

Among sarcomas, gastrointestinal stromal tumors (GISTs) have a special position, being the most common nonepithelial tumors of the gastrointestinal mesenchyme. They are characterized by gastrointestinal primary disease, typical microscopic morphology and expression of the KIT protein. For several years, there was little progress or interest in this field, surgical resection remained the treatment most commonly used and outcomes remained suboptimal. Generally only about half (54%) of patients with primary nonmetastatic GIST survived for 5 years even after complete resection and the risk of recurrence at 2 years remained a high 40%. [2]

The first recent breakthrough was the realization that these tumors are characterized by KIT or PDGFRA receptor tyrosine kinase mutations in up to 85% of cases. With the advent of the oral tyrosine kinase inhibitor (TKI) therapy, the management of this disease has undergone a virtual revolution. The first attempt to develop guidelines for management of GIST took place in 2002. [3]

The role of such MDT approach is well established in oncology. What is less well known is that, for GIST, this concept was initiated way back in 2004 at the consensus conference organized by european society for medical oncology (ESMO) in Milan. [4] Here an expert panel included pathologists, molecular biologists, radiologists, surgical oncologists, medical oncologists, experts in formulating clinical practice guidelines, general surgeons, and a statistician. Invited participants were representatives from sarcoma societies in Europe and USA. This group was able to identify a total of 32 consensus points, based on Standard Options Recommendations (SOR) of the French National Federation of Cancer Centers (FNCLCC), and National Comprehensive Cancer Network (NCCN) [Table 1]. [5]
Table 1: Key Consensus Points from the Multi Disciplinary Team GIST Consensus Conference 2004 versus current recommendations

Click here to view


Since then, clinical trials continue to provide data demonstrating the efficacy and safety of TKIs. [6] This has resulted in several changes in global guidelines and consensus about the optimal management of GIST. Because of fast paced developments in the field guidelines have required regular revisions (NCCN guidelines were updated in 2007, 2010, and 2011). [7] Knowledge of key genetic events driving pathogenesis, emergence of drug resistance, and identification of mutations driving recurrence/disease progression are some of the factors that have been responsible for changes in guidelines. [8]

GIST as an ideal candidate for the MDT approach

Until a few years ago, GIST was almost exclusively in the domain of surgical oncologists because of its chemoresistant nature and lack of systemic therapy options. However, with better understanding of natural history, underlying pathophysiology, driving genetic aberrations, and more accurate radiological/metabolic staging, a multidisciplinary team of surgeons, medical oncologists, radiologists, pathologists, molecular pathologists, and counselors are imperative for optimal diagnosis, management, and follow-up.

GIST is a disease of older individuals and both sexes with median age at diagnosis of about 60-65 years and approximately 50% patients being females. [9],[10] They are commonly found in the stomach (39-65%),small intestine (21-43%), and colorectal region (2-15%). A high index of diagnostic suspicion is required of the MDT since a fifth of GIST patients are asymptomatic at diagnosis and others present with nonspecific symptoms like abdominal discomfort, gastrointestinal bleeding, bowel obstruction, general debility, and fatigue. [11],[12]

The most common diagnostic tests prior to confirmatory biopsy include computed tomography (CT) scan (76%), endoscopy (24%), and ultrasonography (USG) (12%) highlighting the significant contribution of an imaging specialist in the work-up of these patients. More recently metabolic imaging using positron emission tomography and computed tomography (PET-CT) has been found to be very sensitive and specific for initial staging and response to TKI therapy. [13]

Because GIST are usually soft fragile tumors the biopsy procedure has the potential to result in tumor hemorrhage and tumor dissemination, which impacts adversely on the outcome. There is general consensus that an endoscopic ultrasound (EUS) biopsy is better than percutenous biopsy in these circumstances.

Once a biopsy tissue is available for pathological testing, in addition to routine microscopy, ancillary useful techniques include immunohistochemistry (IHC), conventional cytogenetics, electron microscopy, and molecular genetics, especially fluorescence in situ hybridization (FISH) and polymerase chain reaction (PCR) based methods. IHC demonstrates CD117 (KIT) positivity in more than 95% cases and is used in the majority of patients (94%). [14] This is an example of appropriate implementation of the current guidelines. Furthermore, there is now well established role of mutational analysis of the KIT receptor, especially those in exons 9, 11, 13, and 17, which can be used to select appropriate therapy and predict outcome by the MDT. [15] And finally the use of GIST directed systemic therapy with imatinib and other TKIs have cemented the role of the medical oncologist. The addition to the armamentarium of the MDT has resulted in dramatic changes in survival and quality of life (QoL).

The core MDT in GIST should consist of all experts that have the ability, experience, and training to contribute to the following key management issues:

  • Diagnosis and initial work-up (including endoscopy, imaging, pathology, molecular pathology, prognostic factors)
  • Surgical management
  • Neoadjuvant and adjuvant therapy
  • Follow up and timely evaluation of suspected relapse
  • Treatment of relapsed, metastatic and advanced disease
The invited participants of the 2004 ESMO Consensus Conference in Milan continue to represent the core members of the GIST MDT - pathologists, molecular biologists, radiologists, surgical oncologists, and medical oncologists. [4] To this list we should add a gastroenterologist, an oncology nurse, and a counselor/patient advocate.

The MDT will be familiar with the fact that at initial diagnosis, 82% of patients have localized disease. Registry data from US shows no change in this trend over the years. About 15-18% patients present with metastatic disease and a similar number develop metastasis subsequently. In both cases, the common site of metastasis is liver (63.5%) and peritoneum (45.9%). In patients presenting with a small submucosal tumor, the diagnostic approach is based on whether endoscopic biopsy is possible or not. When an endoscopic biopsy is possible, it is preferred over "blind" closed biopsy. The decision making is more complicated when tumor is not amenable to endoscopic biopsy. Should a transabdominal biopsy be done at the risk of spilling malignant cells before definitive surgery? This risk has to be balanced against performing a potentially mutilating surgical procedure for a benign tumor or one that can be cured by other modes of therapy (e.g., germ cell tumors or non hodgkins lymphoma (NHL)). This decision is taken collectively by the gastroenterologist, surgical oncologist and radiologist in the MDT.

The next step is close cooperation between the pathologist, the cytogeneticist, and the molecular biologist. CD117 positivity is almost considered necessary for the diagnosis of GIST, being seen in > 95% of tumors by IHC. The KIT protein is expressed on the cell surface and a tyrosine kinase receptor activating mutation in its gene are found in 80-85% cases, exon 9, 11, 13, and 17 being commonly involved. [15],[16] The remaining tumors exhibit mutations of the PDGFRA gene (5-7% of patients), being commonly found in gastric tumors and predict a more indolent clinical course. [17]

Unfortunately, clinical application of this knowledge is still suboptimal. Mutation analysis is actually carried out only in 6% of cases - 12% in academic centers versus 1% in community-based practices. [14] The molecular biologist will also contribute in distinguishing sporadic GIST (activating kinase mutations involving KIT or PDGFRA) with the familial GIST (Carney Startakis syndrome), which has Krebs cycle mutations involving the SDH subunits. Updated guidelines recommend mutational testing to confirm the diagnosis of GIST. [18] Such analysis will give important prognostic information to the MDT. [19] The Gastrointestinal Stromal Tumor Meta-Analysis Group (MetaGIST) reconfirmed that exon 9 mutations have prognostic and therapeutic significance. [20],[21] The revised recommendation is to use higher dose of imatinib (800 mg/day) for KIT exon 9 activating mutations (vide infra; based on subgroup analysis of EORTC STBSG 62005 Phase III Study).

For patients whose biopsy confirms the diagnosis of GIST, the next steps have been recently modified as per the NCCN Guidelines Version 3.2012. [22] This NCCN guidelines panel members also included orthopedic oncologists, pediatric oncologists, BMT specialist and internists - primarily because they included all sarcomas. For GIST patients, it recommends shared decision making based on histology, abdominal and pelvic CT with contrast or MRI and chest imaging. Selected patients may also require EUS and conventional flexible endoscopic evaluation. For gastric GIST tumors that are less than 2 cm in size, fine needle aspiration cytology is recommended under EUS guidance. They should also undergo abdominal and pelvic CT scan with contrast. If the MDT finds no high risk features on EUS, the patient can be offered regular endoscopic surveillance every 6-12 months. If, in contrast, there are high risk EUS features, the guidelines recommend complete surgical resection followed by regular imaging (CT) evaluation every 3-6 months for the next 5 years and annually thereafter.

The MDT will also debate whether RECIST criteria are adequate for evaluating response to therapy in GIST tumors. In the EORTC STBSG 62005 study, the OS was evaluated based on the diseases status at 6 months, being similar for patients with Complete remission (CR), Partial remission (PR), and Stable disease (SD). [23] Hence the revised guidelines recommended use of size and tumor density on CT scan for evaluating response. They also recommended FDG-PET when early assessment of response is necessary in the neoadjuvant setting - but not as standard of care. Use of contrast enhanced USG is also useful particularly for tumor vascularization. [24] Curiously, an early sign of progression could be development of an intratumoral nodule that reflects as increase in tumor density.

GIST surgery requires that the tumor is removed en bloc with the surgical specimen. However, radical excision involving entire anatomical compartments is not usually recommended. The standard of care is surgical wide excision sufficient to result in negative margins (R0). This implies ensuring that the tumor is removed with a rim of normal tissue. One centimeter of rim is the cut-off used in several studies. The margin may be much smaller in reality due to surgical limitations and are acceptable if anatomical barriers exist, for example, near critical neurovascular structures. If there is such a possibility, it is recommended that the tumor be inked and surgical clips be placed to help guide the pathologists and potential future surgery (revision) or radiotherapy. Once surgical resection is the decision, patients whose tumor allows complete resectability without significant morbidity or sequelae should undergo the procedure right away.

GIST tumors fall into four prognostic categories based on risk of recurrence based on the Armed Forces Institute of Pathology classification (AFIP). [25] They are very low, low, intermediate and high risk. The two important features are size of primary tumor and the mitotic rate expressed per 50 high power fields (HPF). [15] Other features of prognostic importance include location of tumor, whether R0 resection was achieved or tumor rupture/spillage took place.

If high risk features are absent, the patient is put on a surveillance plan (vide supra).

Being chemoresistant tumors, for several decades the prognosis of GIST remained poor and high risk patients did not have many options beyond R0 resection. In the recurrent or metastatic setting, the median overall survival (OS) ranged from 9 to 18 months, there being no chance of cure even after complete surgical removal of the lesions. [15]

All this changed with the availability of imatinib. This is the first molecule that was designed specifically as a competitive inhibitor of the signal transduction pathway by blocking a specific protein tyrosine kinase. [26] One meta-analysis of the electronic databases up to 2009 included one randomized controlled trial (RCT), three phase II studies, three cohort studies, and nine case reports showed high risk of recurrence in patients with surgically resected GIST. The 1-year recurrence-free survival was estimated to be 98% [95% confidence interval (CI), 96-100] in the imatinib group versus 83% (95% CI, 78-88) in the placebo group. This amounts to a 65% reduction in recurrence risk (hazard ratio, 0.35; 95% CI, 0.22-0.53; P < 0.0001) and an absolute recurrence-free survival difference of 15% at 1 year in KIT positive localized GIST. [27]

With the approval of imatinib in 2002, patients the median progression free survival (PFS) improved to 20-24 months and median OS to 50-58 months in patients with resected GIST. Hence following R0 resection, the MDT has the option of considering adjuvant imatinib therapy for patients whose tumor shows high risk features. [Table 2] summarizes the activity of imatinib against various tyrosine kinases.
Table 2: Activity of imatinib mesylate against selected tyrosine kinases.

Click here to view


After a single daily oral dose of 400 mg, the drug bioavailability is 98%, protein binding is 95%, peak plasma levels occur within 2-4 hours and it is not affected by food intake. Dose of 600 mg daily results in steady state AUC that is 1.2 times higher than that for 400 mg daily dose. Although higher clearance occurs in males and those with high Hb levels, once daily dose is sufficient in all patients. Imatinib is subject to hepatic metabolism. Drugs that are metabolised by CYP3A, CYP2D6, and CYP2C9 compete with imatinib and can increase plasma levels of either or both drugs. It is eliminated through the fecal route with 30% of the drug being unchanged.

In the Phase II Z9000 study conducted by the American College of Surgeon Oncology Group (ACOSOG), there were 107 KIT positive GIST patients with complete gross resection (less than five satellite peritoneal metastases) who were high risk (primary tumor > 10 cm or rupture at surgery) of recurrence. [28] With one year of imatinib (400 mg/day), the 3 year recurrence free survival improved to 61% compared with historical 5-year survival of 20%. Because of this and other similar datasets, imatinib has become the gold standard for management of advanced CD117 positive GIST since 2003. [29]

Once the decision to give adjuvant imatinib therapy is taken, the medical oncologist will lead the discussion in the MDT. He will guide the others on several key questions. These include dose, duration, and purpose of the adjuvant therapy. The large pivotal Phase III trials (S0033 and EORTC/ISG/AGTG 62005 studies) compared the 'standard' 400 mg once-daily dosing of imatinib to 400 mg twice-daily dosing (800 mg/day). That study showed that the RR and OS were identical in the two arms. Two international Phase III adjuvant trials (EORTC 62024 and SSG/AIO XVIII studies), in which patients who have undergone complete gross resection (R0-R1) of a localized GIST classified as intermediate or high risk of malignancy (tumor size ≥5 cm and/or mitotic count ≥5/HPF) have evaluated the role of adjuvant imatinib.

The European EORTC 62024 recruited 750 patients till 2008. In this study complete resection (no marginal disease or mets), was followed by randomizing patients between 400 mg imatinib for 2 years or no treatment (which was the standard of care arm). [30] Its question is to identify the role of imatinib in long-term survival. Hence the patients will be followed up for years before the final results become available. [30]

In contrast, the phase III SSGXVII/AIO trial demonstrated improved overall survival with 36 months of adjuvant imatinib (92%) when compared with patients receiving it for 12 months (81.7%). Even the 5 years' recurrence-free survival favored the longer duration of adjuvant imatinib (65.6% for 36 months versus 47.9% for the control arm). [31]

Another phase III trial compared continuous versus interrupted imatinib therapy beyond 1 year of treatment in patients with advanced GISTs. [32] When data showed progressive disease in 26 out of 32 patients (81%) in the interruption arm versus only 8 out of 26 patients in the continuation arm (30%), and the corresponding median PFS after randomization was 6.1 months versus 18 months in the continuation arm (P < 0.0001), ethical considerations compelled amendment in the study protocol to randomize patients after 3 years. Based on reporting of this data, use of IM continuously to patients with advanced GISTs, until disease progression or unacceptable toxicity, has become standard of care.

Interestingly, since the EORTC trial allowed crossover (subset of 133 patients crossing over to 800 mg/day in this study), there is a compelling case to increase dose of IM to 800 mg/day (400 mg twice daily) once there is disease progression on IM 400 mg/day. [33] We feel this should be the current standard of care.

The EORTC-ISG-AGITG 62005 trial showed that patients with KIT exon 9 mutant and wild-type tumors had lower response to IM (34% KIT exon 9 and 25% for wild-type versus 68% for KIT exon 11) that translated into a shorter PFS. [34] Also patients with exon 9 mutation had improved PFS with higher (800 mg/day) dose of imatinib (median PFS of 18 months versus 6 months for the 400 mg/day group).

Wozniac et al, reported also on the tumors bearing exon 9 mutant KIT isoform. [34] This data confirmed that dose increase of IM from 400 to 800 mg daily improved PFS (6 versus 19 months; P = 0.017) and showed tendency to impact OS (28 versus 35 months; P = 0.15). [1],[5],[10],[18] As a result, the NCCN as well as the European Society for Medical Oncology recommended that the dose of 800 mg/day should be used for such patients. [1],[5],[10],[18]

The meta-analysis of the EORTC-ISG-AGITG 62005 and the Intergroup S0033 studies included a total of 1640 patients showed that poor performance status, high neutrophil count, absence of KIT exon 11 mutations and male gender had bearing on OS as well as PFS. [35]

In spite of prolonged therapy with imatinib, there is a high incidence of recurrence or progressive disease in advanced or high risk GIST. Mechanisms of such secondary resistance are heterogeneous both across patients and inside the same patient. [36],[37],[38] For instance, Wardelmann et al, showed that resistance to imatinib was associated with the same primary mutations but different secondary mutations in different lesions in the same patient. [37] In contrast, Liegl et al, used the sensitive techniques of allele-specific PCR to show the presence of more than one secondary mutation in a single progressing lesion. [38]

Clear understanding of the above points and consensus among the MDT will enable to nurse practitioner and the counselor/patient advocate to complement the communication between the medical oncologist and the patient.

To better understand the overall prognosis in the imatinib era, a Phase III BFR14 trial was conducted by the French Sarcoma Group. [39] They studied 236 of the 434 patients enrolled, who had received IM 400 mg daily for at least 5 years. Long-term nonprogressors included gastric GIST, PS 0 (P=0.04), patients with small tumors (median 49 mm versus 102; P=0.003), absence of peritoneal disease and exon 11 mutation that generally involved codons 557 and/or 558.

For tumors where R0 resection seems unlikely, the patient is recommended preoperative/neoadjuvant imatinib. This option is also offered in case the timing of the surgery needs to be deferred for nonmedical reasons. The drug is usually given in the dose of 400 mg daily for prolonged periods (6-12 months).

If the patient had received neoadjuvant imatinib, he should continue receiving it postoperatively (in the adjuvant setting) in case there was documentation of objective response preoperatively.

For patients who present with an R1 resection, revision surgery at a high volume reference centers is recommended. An experienced MDT is ideally placed to achieve adequate margins without major morbidity. The decision needs to be individualized based on several factors including tumor extent and tumor biology. Those who have R1 resection and had not received imatinib in the neoadjuvant setting should be commenced in imatinib immediately. If, however, such a patient was already on neoadjuvant imatinib (for adequate length of time) and still could not achieve R0 resection, imatinib should be continued, dose escalated or the patient switched to sunitinib while planning for revision resection.

For patients with gross residual disease (R2 resection), reoperation is mandatory as a general rule. If the tumor is such that adequate margins cannot be achieved or surgery is likely to be mutilating, neoadjuvant therapy should be given. If already on imatinib, the patient should be continued on it while evaluating for possibility of reresection. The MDT will also evaluate whether change to other TKIs is applicable or not.

In the second line setting, one option is to double the dose of imatinib. Unfortunately, this is associated with almost doubling of toxicity (Grade 3 and 4 toxicity being 63% versus 43%), four times higher dose reduction (60% versus 16%) and greater treatment interruptions (64% versus 40%). [40],[41] In revised guidelines Sunitinib is effective and well tolerated in IM refractory patients at standard dose of 50 mg/day. Dose reduction to 37.5 mg/day continuously may also be equally effective and better tolerated.

The option of sunitinib therapy for GIST became a reality after its approval in 2006 for the treatment of advanced IM-resistant GIST or for patients that are IM-intolerant. [42]

For patients with progressive disease the decision is based on whether there is limited or extensive systemic disease. If limited, the patients dose of imatinib can be increased or treatment changed to sunitinib. Efficacy and safety of sunitinib (37.5 mg daily) versus imatinib (800 mg daily) was being evaluated in a Phase IIIb study. [43] Unfortunately this was terminated early due to poor recruitment and operational futility.

Currently several other TKIs (such as nilotinib, dasatinib, and sorafenib) and their combinations are showing promise [Table 3]. They are usually considered only after patient has developed progressive disease while on the two approved agents.
Table 3: New Agents and protocols under investigation for metastatic GIST

Click here to view


Phase III trials are underway with nilotinib and masitinib. One Phase III study of Nilotinib in IM and SU resistant GIST failed to show benefit. On the contrary, data from another disease (treatment-naive CML) indicates that it is more effective than IM, providing faster, deeper, and longer lasting response. [26] Masitinib is a potent inhibitor of KIT, PDGFRA, and FGFR3. Results of a Phase II trial in advanced GISTs at 9 months of median follow-up showed 19 out of 21 evaluable patients (90%) had either partial response or stable disease [44] (ref 2007 Annual ASCO meeting). Dasatinib, an inhibitor of KIT, PDGFRA, and SRC is in a first line Phase II trial for advanced GIST. Interestingly, this drug is active against specific imatinib and SU-resistant KIT and PDGFRA mutants. [45]

Other options include radiofrequency ablation (RFA), chemoembolization, and palliative RT. If the disease continues to progress the patient may be offered entry into a clinical trial. Continuing current therapy after PD may slow progression and is also an option when clinical trial is not available for the patient. The only other option is best supportive care.

If the patient has extensive systemic disease at initial diagnosis, local therapy is not an option. Here we take into consideration that the original ESMO guidelines for GIST (2005) were revised in 2009. Up to 85% of metastatic GIST survive at 2 years with optimal therapy. Of these, 4% are intolerant to IM and half will develop resistance to IM within 2 years. Of these 70% are due to specific second mutations within KIT. Resistance to imatinib can be treated surgically (focal tumor) or alternate kinase inhibitors (like Sutent for multifocal resistance). The new guidelines remain unchanged for standard treatment for unresectable or metastatic GIST in the first line - 400 mg/day.

Surgery for residual disease after imatinib for metastatic disease remains investigational. There is inclination for the use of imatinib in the neo-adjuvant setting - in tune with the NCCN guidelines. Imatinib is recommended in adjuvant and neoadjuvant setting. [46]

Crenolanib (CP-868596) is an oral drug being evaluated in the management of D842V PDGFRA metastatic mutant GIST. It seems to be effective in blocking activity of single or compound PDGFRA D842V mutant kinases, even in the case of PDGFRA V561D + D842V and PDGFRA T6741 + D842V - mutations against which imatinib and sunitinib have no action. [47] Regorafenib is another TKI with activity against several kinases including KIT, PDGFR, FGFR, VEGFR2 and 3, TIE-2, and BRAF. Among the 33 patients enrolled in this study, data was available on 22 patients who had been on the protocol for at least 16 weeks. Of these, 19 were without disease progression after four cycles of study drug dosing. Benefit was among patients who had primary KIT exon 11 mutations, KIT exon 9 mutations or wild-type kinase genotype. [48] Interestingly this drug leads to significant change of the metabolic response early (from the first dose) on PET scan analysis. [49]

Patient advocacy groups

Over the past decade, GIST patient advocacy groups have been playing an increasingly active role. At the forefront are the GIST Support International and Global GIST Network. In fact, representatives from as many as 23 GIST patient advocacy organizations from all over the world met in Bad Nauheim, Germany for a conference in mid 2007. They agreed upon and signed an international declaration to support state-of-the-art GIST treatment and care as a right for each and every GIST patients. [50]

Familial versus sporadic GIST

There is some debate on the prevalence of hereditary GIST susceptibility in adults with GIST. [51] Project FLAG, an ongoing multicenter study attempts to address this. Patients with confirmed GIST were recruited through sarcoma clinics at MSKCC and DFCI as well as a web recruitment tool. Of the 512 enrolled participants, specimens from 92 high-risk and 41 low-risk subjects were analyzed. Only eight mutations were found in KIT and none in PDGFRA. Preliminary data indicates that hereditary GIST forms only a small fraction, individuals with GIST and without a family history of GIST in other relatives, being unlikely to carry inherited susceptibility linked to the KIT or PDGFRA protooncogenes.

The MDT will also be able to discuss the differential diagnosis of Carney Triad with patients. [52] This refers to presence of at least two of the following tumor types:

  • GIST
  • Pulmonary chondroma
  • Extra-adrenal paraganglioma
  • Adrenocortical adenoma (a benign tumor of the adrenal gland)
  • Esophageal leiomyoma (a benign tumor of the esophagus).
Though an extremely rare syndrome (less than 30 cases have been reported having the first three of the tumor types, there is sufficient information to guide the discussion with the patients. For instance, Carney triad is seen in females (85% of cases), with the first tumor diagnosed before the age of 30 years (90% of patients). Only one tumor type is identified at initial presentation (65% of cases), this commonly being a gastric GIST. In the 79 patients reported in 1999, 22% eventually developed all three of the tumor types, while 53% showed GIST and chondroma and 24% showed GIST and paraganglioma. The median interval between the appearance of the first and subsequent tumors is 6 years, the longest being more than 20 years. Carney triad is not a familial disease and is not passed on from generation to generation. The GISTs in Carney triad usually occur inside the stomach, are usually multi-focal and positive for CD117, behave less aggressively than typical sporadic GIST, has less tendency to metastasize and patients even live for many years thereafter. [52]

Current role of the MDT

Optimizing management of GIST clearly requires a MDT approach.

The gastroenterologist will be able to provide a high index of suspicion for the early diagnosis of GIST. He will be able to facilitate and perform EUS and endoscopic biopsies as appropriate. He will also follow up patients to monitor outcome, particularly for those with tumors less than 2 cm in size and especially the low risk ones not requiring treatment.

The pathologist is crucial to confirm the pathological diagnosis of GIST. This requires accurate microscopic examination coupled with appropriate IHC. The pathologist will also help determine the prognosis of the patient based on site and size of the tumor, its surgical margins and mitotic index as well as association with other tumor types.

The imaging specialist and the interventional radiologist have increasing roles in the ideal management of GIST. Selection of the most appropriate imaging tool (CT scan, contrast CT scan, MRI, PET-CT, EUS) helps in the correct staging of disease. They will also determine operability, early response as well as early progression, allowing the MDT to individualize selection of the best treatment option. With emerging evidence that tumor reduction based on RECIST criteria alone does not give the whole picture, the role of the radiologist is evolving rapidly. Tumor density, occurrence of nodule within tumor and early metabolic changes using PET-CT are able to accurately predict response to therapy before changes in tumor size become evident.

The surgeon/ surgical oncologist continue to play a vital role in GIST, tumor resection continuing to remain the standard of care for localized disease. Their role is increasingly being facilitated by the radiologist (to define R0 resection operability), the medical oncologist (converting inoperable or borderline operable cases into those that enable R0 resection using neoadjuvant therapy) and the pathologist (identifying tumor margins, matching them with surgical specimens and guiding revision surgery when required).

The medical oncologist has a significant role in almost all the patients, with the documented usefulness of adjuvant as well as neoadjuvant cancer directed systemic therapy. Fine-tuning of the treatment recommended in major guidelines require the use of appropriate mutation analysis. For instance, patients with some mutations required higher dose of imatinib, whereas other mutations require different oral TKIs. In addition, duration of therapy will be determined based on prognostic features, early indicators of response, follow up imaging and tolerability of treatment. At disease progression, it will also facilitate the selection of the best second line therapy as well as suitability for entry into clinical trials.

Effective communication has gained importance with today's patients being better informed and more interested in active participation in the decision making process. Nurses, counselors, and patient advocacy/support groups therefore have an increasing role in ensuring that diagnosis and prognosis are understood, management options are discussed to the patient's satisfaction, his views and preferences guide the treatment path, he complies with oral medication on a long-term regular basis, he remains aware of the progress of the disease and actively participating in regular follow-up.


 » Conclusions Top


Aggressive research, better understanding of the disease and availability of new treatment options have dramatically influenced current guidelines in the management of GIST. The next 5 years will see continuation of this trend. Maturing data from ongoing trials, better understanding of the pathophysiology, identification of new mutations that influence drug resistance and emerge with tumor progression will guide duration, dose and combination of TKi therapy in the adjuvant, neoadjuvant and metastatic setting. There shall be increasing acceptance of individualized therapy to obtain optimal outcome for each GIST patient. The role of alternate strategies for imatinib resistance will get crystallized. At the same time data from novel agents will necessitate the modification of existing guidelines to match the pace of emerging evidence. The MDT will therefore have increasingly vital role to play and will have to expand to involve other stake holders, making the experience of the patient less stressful and more satisfying.

At the same time, several questions remain unanswered (and some may continue to remain so). Although PET-CT is recommended by some, analysis of large clinical trial data showed that RECIST criteria continue to remain good predictors of outcome and conventional imaging should be regarded as a satisfactory method of assessment, provided that the radiologist has experience with GIST.

The impact of TKIs on the OS remains a real concern. In the Z9001 study, the curves for relapse-free survival seem to converge beyond 30 months. We might never know the real impact since the independent review committee has advocated crossover.

Other unanswered questions include the optimal duration of therapy, the role of the genotype and the optimal dose of adjuvant IM. The French Sarcoma Group trial BFR14 showed that IM should be continued until disease progression, especially in advanced disease setting. Does KIT or PDGFRA mutations predict the benefit of adjuvant IM? For instance patients with PDGFRA D842V or KIT exon 9 mutation (IM resistance) may not benefit from adjuvant as much as patients with KIT exon 11 mutations. Also should patients with KIT exon 9 mutations receive 400 or 800 mg/day of IM remains unclear. Data from ACOSOG Z9001 and other adjuvant trials will hopefully resolve this dilemma.

Based on data from trials in the metastatic setting, it is likely that patients with high-risk disease (large tumors, preoperative tumor rupture) will require longer durations of adjuvant treatment (3 years or maybe longer). Wild-type and PDGFRA mutant tumors that seem to have a spontaneously favorable outcome may not derive as much benefit from adjuvant IM as KIT exon 11 and KIT exon 9 mutant GIST, which respond well to therapy and have a poorer prognosis following surgical resection alone. Therefore, the indication of adjuvant IM may not be maintained in all patients' subgroups. Thus the optimal management of GIST will remain a dynamic process that requires a committed MDT.

 
 » References Top

1.Demetri GD, von Mehren M, Antonescu CR, DeMatteo RP, Ganjoo KN, Maki RG, et al. NCCN Task Force report: Update on the management of patients with gastrointestinal stromal tumors. J Natl Compr Canc Netw 2010;8 Suppl 2:S1-41.  Back to cited text no. 1
    
2.DeMatteo RP, Lewis JJ, Leung D, Mudan SS, Woodruff JM, Brennan MF. Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival. Ann Surg 2000;231:51-58.  Back to cited text no. 2
    
3.Judson I, Leahy M, Whelan J, Lorigan P, Verrill M, Grimer R, et al. A guideline for the management of GIST. Sarcoma 2002;6:83-7.   Back to cited text no. 3
    
4.Blay JY, Bonvalot S, Casali P, Choi H, Debiec-Richter M, Dei Tos AP, et al. Consensus meeting for the management of gastrointestinal stromal tumors. Report of the GIST Consensus Conference of 20-21 March 2004, under the auspices of ESMO. Ann Oncol 2005;16:566-78.  Back to cited text no. 4
    
5.Demetri GD, Benjamin RS, Blanke CD, Blay JY, Casali P, Choi H, et al. NCCN Task Force report: management of patients with gastrointestinal stromal tumor (GIST)--update of the NCCN clinical practice guidelines. J Natl Compr Canc Netw 2007;5 Suppl 2:S1-29.  Back to cited text no. 5
    
6.Verweij J, van Oosterom A, Blay JY, Judson I, Rodenhuis S, van der Graaf W, et al. Imatinib mesylate (STI-571 ImatinibwGleevec) is an active agent for gastrointestinal stromal tumours, but does not yield responses in other soft-tissue sarcomas that are unselected for a molecular target. Results from an EORTC Soft Tissue and Bone Sarcoma Group phase II study. Eur J Cancer 2003;39:2006-11.  Back to cited text no. 6
    
7.National Comprehensive Cancer Network (NCCN) guidelines. Available from: http://www.nccn.org [Last accessed on 2011 Jul 06].  Back to cited text no. 7
    
8.Attili SV, Ananda B, Mandapal T, Anjaneyulu V, Sinha S, Reddy OC. Factors influencing progression-free survival in gastrointestinal stromal tumors with special reference to pathologic features, cytogenetics, and radiologic response. Gastrointest Cancer Res 2011;4:173-7.  Back to cited text no. 8
    
9.Dematteo RP, Lewis JJ, Leung D, Mudan SS, Woodruff JM, Brennan MF. Two hundred gastrointestinal stromal tumors: Recurrence patterns and prognostic factors for survival. Ann Surg 2000;231:51-8.  Back to cited text no. 9
    
10.Casali PG, Blay JY. (On behalf of the ESMO/ CONTICANET/ EUROBONET Consensus Panel of experts): Soft tissue sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up Ann Oncol 2010;21 (Suppl 5):v198-203.  Back to cited text no. 10
    
11.Miettinen M, Furlong M, Sarlomo-Rikala M, Burke A, Sobin LH, Lasota J. Gastrointestinal stromal tumors, intramural leiomyomas, and leiomyosarcomas in the rectum and anus: A clinicopathologic, immunohistochemical, and molecular genetic study of 144 cases. Am J Surg Pathol 2001;25:1121-33.   Back to cited text no. 11
    
12.Miettinen M, Sobin LH, Lasota J. Gastrointestinal stromal tumors of the stomach: a clinicopathologic, immunohistochemical, and molecular genetic study of 1765 cases with long-term follow-up. Am J Surg Pathol 2005;29:52-68.   Back to cited text no. 12
    
13.Choi H, Charnsangavej C, Faria SC, Macapinlac HA, Burgess MA, Patel SR. et al. Correlation of computed tomography (CT) and positron emission tomography (PET) in patients with metastatic GIST treated at a single institution with imatinib mesylate: proposal of new CT response criteria. J Clin Oncol 2007;25:1753-9.  Back to cited text no. 13
    
14.Pisters PW, Blanke CD, von Mehren M, Picus J, Sirulnik A, Stealey E, et al. (reGISTry Steering Committee). A USA registry of gastrointestinal stromal tumor patients: Changes in practice over time and differences between community and academic practices.Ann Oncol 2011;22:2523-9.  Back to cited text no. 14
    
15.Cassier PA, Blay JY. Imatinib mesylate for the treatment of gastrointestinal stromal tumor. Expert Rev. Anticancer Ther 2010;10:623-34.   Back to cited text no. 15
    
16.Heinrich MC, Corless CL, Demetri GD, Blanke CD, von Mehren M, Joensuu H, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 2003;21:4342-9.  Back to cited text no. 16
    
17.Corless CL, Schroeder A, Griffith D, Town A, McGreevey L, Harrell P, et al. PDGFRA mutations in gastrointestinal stromal tumors: Frequency, spectrum and in vitro sensitivity to imatinib. J Clin Oncol 2005;23:5357-64.  Back to cited text no. 17
    
18.Casali PG, Jost L, Reichardt P, Schlemmer M, Blay JY. Gastrointestinal stromal tumors: ESMO Clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 2008;19(Suppl 2):ii35-8.  Back to cited text no. 18
    
19.Debiec-Rychter M, Sciot R, Le Cesne A. KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumors. Eur J Cancer 2006;42:1093-103.  Back to cited text no. 19
    
20.Gastrointestinal Stromal Tumor Meta- Analysis Group (MetaGIST): Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors: a meta-analysis of 1,640 patients. J Clin Oncol 2010;28:1247-53.   Back to cited text no. 20
    
21.Kho PK, Chua W, Moore MM, Clarke SJ. Is it prime time for personalized medicine in cancer treatment? Per Med 2010;7:387-97.   Back to cited text no. 21
    
22.www.nccn.org soft tissue sarcoma guidelines ver 3.2012 Available from: http://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf [Last accessed on 2012 Jul 06].  Back to cited text no. 22
    
23.Le Cesne A, Van Glabbeke M, Verweij J, Casali PG, Findlay M, Reichardt P, et al. Absence of progression as assessed by response evaluation criteria in solid tumors predicts survival in advanced GI stromal tumors treated with imatinib mesylate: The intergroup EORTC-ISG-AGITG phase III trial. J Clin Oncol 2009;27:3969-74.  Back to cited text no. 23
    
24.Lassau N, Lamuraglia M, Chami L, Leclère J, Bonvalot S, Terrier P, et al. Gastrointestinal stromal tumors treated with imatinib: Monitoring response with contrast-enhanced sonography. AJR Am J Roentgenol 2006;187:1267-73.  Back to cited text no. 24
    
25.Miettinen M, Sobin LH, Lasota J. Gastrointestinal stromal tumors of the stomach: A clinicopathologic, immunohistochemical, and molecular genetic study of 1765 cases with long-term follow-up. Am J Surg Pathol 2005;29:52-68.  Back to cited text no. 25
    
26.Vaid A. Nilotinib as first-line therapy for chronic myeloid leukemia. Indian J Cancer 2011;48:438-45.   Back to cited text no. 26
[PUBMED]  Medknow Journal  
27.Essat M, Cooper K. Imatinib as adjuvant therapy for gastrointestinal stromal tumors: A systematic review. Int J Cancer 2011;128:2202-14.  Back to cited text no. 27
    
28.McCarter MD, Antonescu CR, Ballman KV, Maki RG, Pisters PW, Demetri GD, et al: Microscopically positive margins for primary gastrointestinal stromal tumors: Analysis of risk factors and tumor recurrence. J Am Coll Surg 2012;215:53-9.  Back to cited text no. 28
    
29.Jong FA, Werweij J. Role of imatinib mesylate (Gleevec/ Glivec) in GIST. Expert Rev Anticancer Ther 2003;3:757-66.  Back to cited text no. 29
    
30.Essat M, Cooper K. Imatinib as adjuvant therapy for gastrointestinal stromal tumors: A systematic review. Int J Cancer 2011;128:2202-14.  Back to cited text no. 30
    
31.Joensuu H, Eriksson M, Sundby Hall K, Hatrmann J, Pink D, Schutte J, et al. Twelve versus 36 months of adjuvant imatinib (IM) as treatment of operable GIST with a high risk of recurrence: Final results of a randomized trial(SSGXVIII/AIO). JAMA doi: 10.1001/jama.2012.347 (ahead of print).   Back to cited text no. 31
    
32.Blay JY, Le CA, Ray-Coquard I, Bui B, Duffaud F, Delbaldo C, et al. Prospective multicentric randomized Phase III study of imatinib in patients with advanced gastrointestinal stromal tumors comparing interruption versus continuation of treatment beyond 1 year: The French Sarcoma Group. J Clin Oncol 2007;25:1107-13.  Back to cited text no. 32
    
33.Zalcberg JR, Verweij J, Casali PG, Le Cesne A, Reichardt P, Blay JY, et al. Outcome of patients with advanced gastro-intestinal stromal tumours crossing over to a daily imatinib dose of 800 mg after progression on 400 mg. Eur J Cancer 2005;41:1751-7.  Back to cited text no. 33
    
34.Wozniak A, Floris G, Debiec-Rychter M, Sciot R, Schöffski P. Implications of mutational analysis for the management of patients with gastrointestinal stromal tumors and the application of targeted therapies. Cancer Invest 2010;28:839-48.   Back to cited text no. 34
    
35.Van Glabbeke MM, Owzar K, Rankin C, Simes J, Crowley J, GIST Meta-analysis Group. Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors (GIST): A meta-analyis based on 1,640 patients (pts). J Clin Oncol 2007;25 (18 Suppl.):10004.  Back to cited text no. 35
    
36.Loughrey MB, Waring PM, Dobrovic A, Demetri G, Kovalenko S, McArthur G. Polyclonal resistance in gastrointestinal stromal tumor treated with sequential kinase inhibitors. Clin Cancer Res 2006;12:6205-6.   Back to cited text no. 36
    
37.Wardelmann E, Merkelbach-Bruse S, Pauls K, Thomas N, Schildhaus HU, Heinicke T, et al. Polyclonal evolution of multiple secondary KIT mutations in gastrointestinal stromal tumors under treatment with imatinib mesylate. Clin Cancer Res 2006;12:1743-9.  Back to cited text no. 37
    
38.Liegl B, Kepten I, Le C, Zhu M, Demetri GD, Heinrich MC, et al. Heterogeneity of kinase inhibitor resistance mechanisms in GIST. J Pathol 2008;216:64-74.  Back to cited text no. 38
    
39.Blesius A, Cassier PA, Ray-Coquard IL, et al . Who are the long responders to imatinib (IM) in patients with advanced GIST? Results of the BFR14 prospective French Sarcoma Group randomized phase III trial. J Clin Oncol 2011;29 (Suppl Abstract):10048.   Back to cited text no. 39
    
40.Verweij J, Casali PG, Zalcberg J, LeCesne A, Reichardt P, Blay JY, et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: Randomised trial. Lancet 2004;364:1127-34.  Back to cited text no. 40
    
41.Blanke CD, Rankin C, Demetri GD, Ryan CW, von Mehren M, Benjamin RS, et al. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol 2008;26:626-32.   Back to cited text no. 41
    
42.Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: A randomised controlled trial. Lancet 2006;368:1329-38.  Back to cited text no. 42
    
43.Available from: http://www.clinicaltrials.gov/ct2/show/study/NCT00372567?term=gist+imatinib+sunitinibandrank=4 [Last accessed on 2011 Jul 07].   Back to cited text no. 43
    
44.Le Cesne A, Blay JY, Bui BN, Bouché O, Adenis A, Domont J, et al. Phase II study of oral masitinib mesilate in imatinib-naïve patients with locally advanced or metastatic gastro-intestinal stromal tumour (GIST). Eur J Cancer 2010;46:1344-51.   Back to cited text no. 44
    
45.Dewaele B, Wasag B, Cools J, Sciot R, Prenen H, Vandenberghe P, et al. Activity of dasatinib, a dual SRC/ABL kinase inhibitor, and IPI-504, a heat shock protein 90 inhibitor, against gastrointestinal stromal tumor-associated PDGFRAD842V mutation. Clin Cancer Res 2008;14:5749-58.  Back to cited text no. 45
    
46.Ashraf M, Jha J, Choudhry A, Aggarwal B, Nayak S, Chakraborty J, et al. Neoadjuvant and adjuvant therapy with imatinib for locally advanced gastrointestinal stromal tumors in eastern Indian patients. Asian Pac J Cancer Prev 2011;12:2059-64.  Back to cited text no. 46
    
47.Heinrich MC, Griffith D, McKinley A, Presnell A, Ramachandran A. The effect of crenolanib (CP-868596) on phosphorylation of the imatinib-resistant D842V PDGFRA activating mutation associated with advanced gastrointestinal stromal tumors. J Clin Oncol 2011;29:(Suppl; abstr 10012)  Back to cited text no. 47
    
48.George S, von Mehren M, Heinrich MC, et al . A multicenter phase II study of regorafenib in patients (pts) with advanced gastrointestinal stromal tumor (GIST), after therapy with imatinib (IM) and sunitinib (SU). ASCO Meet Abstr 2011;29(15_suppl):10007.  Back to cited text no. 48
    
49.Van Den Abbeele AD, Tanaka Y, Locascio T, et al . Assessment of regorafenib activity with FDG-PET/CT in a multicenter phase II study in patients (pts) with advanced gastrointestinal stromal tumor (GIST) following failure of standard therapy (Rx). ASCO Meet Abstr 2011;29(15_suppl):10050  Back to cited text no. 49
    
50.Available from: http://www.gistsupport.org/treatments-for-gist/gist-patientsE28099-right-to-treatment.php [Last accessed on 2011 Jul 07].  Back to cited text no. 50
    
51.Rainville IR, Root EJ, Salerno M, et al . Prevalence of hereditary GIST susceptibility in adults with GIST. J Clin Oncol 2011;29:(suppl; abstr 10043).  Back to cited text no. 51
    
52.Carney JA. Gastric stromal sarcoma, pulmonary chondroma, and extra-adrenal paraganglioma (Carney Triad): Natural history, adrenocortical component, and possible familial occurrence. Mayo Clin Proc 1999;74:543-52.  Back to cited text no. 52
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3]

This article has been cited by
1 CD117/c-kit in Cancer Stem Cell-Mediated Progression and Therapeutic Resistance
Brittni Foster,Danish Zaidi,Tyler Young,Mary Mobley,Bethany Kerr
Biomedicines. 2018; 6(1): 31
[Pubmed] | [DOI]
2 Targeted Therapy Management in NSCLC Patients Using Cytology: Experience from a Tertiary Care Cancer Center
Vidya H. Veldore,Shekar Patil,Shilpa Prabhudesai,C. T. Satheesh,H. P. Shashidhara,Naveen Krishnamoorthy,D. Hazarika,R. Tejaswi,Ankita Prabhudev,Radheshyam Naik,Raghavendra M. Rao,B. S. Ajai Kumar
Molecular Diagnosis & Therapy. 2016; 20(2): 119
[Pubmed] | [DOI]
3 Tumor del estroma gastrointestinal como causa de sangrado de tubo digestivo: presentación de un caso
Julio César López-Valdés,Willy Nava-Gutiérrez,Alejandra Astaburuaga-Gómez,Jaime Eduardo Pérez-Perales
Cirujano General. 2015;
[Pubmed] | [DOI]



 

Top
Print this article  Email this article
 

    

  Site Map | What's new | Copyright and Disclaimer
  Online since 1st April '07
  © 2007 - Indian Journal of Cancer | Published by Wolters Kluwer - Medknow