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Gastrointestinal Stromal Tumours (GISTs) – 2014

UPDATED JUNE 2014

1. GENERAL INFORMATION

1.1 Epidemiological data

1.1.1 Incidence

Gastrointestinal stromal tumours (GIST) are rare tumours. Their incidence is around 1.5/100,000 new cases per year (Nilsson 2005). These estimates do not include small GIST incidentally found during diagnostic or therapeutic procedures carried out for other reasons. In most cases, these small GIST are clinically insignificant. All the more, incidence figures cannot include the microscopic GIST which, if searched carefully, might be present in as many as one fifth of gastric specimens at an age >50 years (Kawanowa 2006; Agaimy 2007; Rossi 2010).

1.1.2 Survival

Five-year survival rates around 60% have been reported for localized, surgically treated disease, while metastatic disease had a bad prognosis before the introduction of molecularly targeted therapies. More recently, in fact, the 5-year survival rate is close to 50% in studies on metastatic patients treated with imatinib. Chances of cure in the localised disease setting are highly dependant on some prognostic factors, so that they vary substantially according to mitotic count, tumour size and tumour site (Miettinen 2006).

1.1.3 Age

Median age is around 60 years. More frequent, typical GIST, harbouring mutations of KIT or PDGFRA, occur in adults, with a sharp increase with age. The age distribution, however, is wide, and all ages can be affected. “Pediatric” GIST are rare, marked by gastric origin, occurrence mainly in females, epithelioid morphology, KIT and PDGFRA wild-type genotypes, frequent multifocality, slow growth, nodal metastases (Rink 2009). Pediatric type GIST may also occur in adults, and in this case recapitulate their features in children (Rege 2011).

1.1.3 Sex

There might be a slight male predominance (around 1.5:1).

1.2 Aetiological and risk factors

1.2.1 Predisposing conditions

There are some hereditary conditions, which generally result in the development of multiple GIST, diagnosed earlier than at average age.
Neurofibromatosis: Type 1 neurofibromatosis (NF-1) is the most frequent condition predisposing to GIST (Mussi 2008; Agaimy 2012). Lesions might be detectable in as many as 20% of NF-1 patients, although only 5% might have clinically relevant conditions. GIST are often multiple and more frequently located to the small bowel. There is a slight female predominance. GIST in neurofibromatosis are typically wild-type, while KIT and PDGFRA mutations have been reported only occasionally. In this sense, a typical KIT/PDGFRA-mutated GIST can occur in a person who incidentally carries a NF-1.
Carney triad and Carney-Stratakis syndrome: The Carney-Stratakis dyad (syndrome) is an autosomal dominant condition of males and females, with incomplete penetrance, marked by GIST and paraganglioma and due to germline loss-of-function mutations of the succinate dehydrogenase gene subunit A, B, C and D (Pasini 2008). On the contrary, Carney’s triad is a nonfamilial condition defined by multiple gastric stromal tumours, paraganglioma, and pulmonary chondroma (Zhang 2010). In all these cases, GIST are wild-type for KIT and PDGFRA, and there is a loss of SDHB expression on immunohistochemistry (Janeway 2011). Their prognosis is better than typical GIST, even when the disease has metastatized.
Germline KIT- and PDGFRA-mutated GIST: Germline mutations of KIT (to exons 8, 9, 11, 13, 17) or PDGFRA (exon 18) have been detected in a small number of families worldwide (Postow 2012; Li 2005). Depending on the mutation, urticaria pigmentosa and other hyperpigmented skin lesions may be present, as well as mastocytosis, abnormalities in oesophageal peristalsis.

1.3 Screening and case finding

1.3.1 Screening and case finding

GIST are rare and early diagnosis is difficult. In fact they tend to grow outwards from within the gastrointestinal wall, giving rise to often symptomless abdominal masses. Mucosa may be long spared, and this may prevent early clinical signs such as minor gastrointestinal bleeding. Endoscopic recognition of the disease can be difficult as well, though some early or low-risk cases can be detected this way. Diagnosis is often made at an advanced stage, on radiological recognition of an abdominal mass, or on an emergency basis, because of the sudden onset of gastrointestinal or peritoneal bleeding. No serous marker is available. For all these reasons, screening is unforeseenable and preclinical case finding is difficult.

1.4 Referral

GIST are rare tumours. Thus they should be referred to centres of expertise, having multidisciplinary teams devoted to this disease. In fact, treatment may be multimodal both in the localised and in the advanced disease setting. If diagnosis is made on an emergency basis, the patient should be referred after surgery. Pathologic diagnosis should be reviewed by an experienced pathologist with access to mutational testing.

1.5 Selected reviews

Imaging
Kalkmann J et al (Kalkmann 2012)

Pathology and molecular biology
Foo WC et al (Foo 2012)

Surgery
Bamboat ZM et al (Bamboat 2012)
Bednarski BK et al (Bednarski 2012)

Medical therapy
Casali PG et al (Casali 2012)
Blay JY et al (Blay 2010)

2. PATHOLOGY AND BIOLOGY

2.1 Biological data

2.1.1 Histogenesis

The GIST cell is currently felt to be related to the interstitial cells of Cajal (Hirota 1998; Kindblom 1998). Physiologically, the system of Cajal interstitial cells is involved in the control of gut motility, by providing a connection between the autonomic gut wall innervation and the slow-wave activity of the gut musculature. In fact, interstitial cells of Cajal are known as the gastrointestinal pacemaker cells. Interstitial cells of Cajal express the KIT oncogene product, KIT, which contributes to their function within the gut wall. Stimulation by a ligand, the stem cell factor, is essential for the activation of KIT. This is a type III tyrosine kinase receptor, which dimerizes following stimulation by the ligand, resulting in autophosphorylation, as well as phosphorylation of downstream signal transduction pathways, which in turn give rise to key cellular responses. In 85% GIST, there is evidence of gain-of-function mutations of the KIT oncogene, which result in a constitutively activated KIT receptor (i.e., the receptor is activated also in the lack of its natural ligand), or the PDGFRA (platelet-derived growth factor receptor alfa) oncogene, which results as well in constitutively activated PDGFRA (Miettinen 2006). These mutations are held to be crucial and early pathogenetic events for these tumours, though further cytogenetic alterations probably are required to give rise to the “malignant” phenotype of clinically relevant GIST. Indeed, the apparently high frequency of microscopic GIST as compared to the rarity of clinical GIST supports this notion. Fifteen per cent of GIST are wild-type and are marked by a different natural history, in addition to a different sensitivity to therapies targeting KIT and PDGFRA. Currently, they are felt to comprise some subgroups, such as those related to NF-1 and those related to Carney triad and Carney-Stratakis syndrome.

2.1.2 Mutations

Both KIT and PDGFRA oncogenes are located on the chromosome 4 (4q12). Gain-of-function mutations of KIT in GIST were first described in 1998 (Hirota 1998). At present, mutations of KIT have been recognized in exons 8, 9, 11, 13, 17, while PDGFRA mutations have been recognized in exons 12, 14, 18 (Lasota 2008; Hoeben 2008; Rubin 2007). The relative frequency of these mutations depends on the patient referral, and, mainly, on the patient setting. The mutational status has both a predictive and a prognostic value, with a dissociation between the two. In general, KIT exon 11 mutations are more responsive to Imatinib, but they also confer a worse prognosis. Thus, their prevalence is higher, as high as 70%, in clinical studies on advanced disease, which collect prognostically unfavourable cases. Most of them are gastric, and the morphology is more frequently spindle-cell. KIT exon 9 mutations are sensitive to Imatinib, although they seem better treated with higher doses of the drug, and are sensitive to Sunitinib. Their frequency is around 10%, but is lower in localized disease settings. Their prognosis is worse or similar to exon 11 mutants, but they are more frequent in small bowel lesions, which have a worse prognosis, and have a spindle cell morphology. The same holds true for KIT exon 13 and 17 lesions. The former underlie <5% of cases and the latter are very rare. On the contrary, PDGFRA mutations entail a better prognosis, so that their incidence may be <5% in advanced series, versus 10-20% in the localized disease setting. Indeed, many correspond to the previously labelled gastric leiomyoblastomas. They are typically gastric and have an epithelioid morphology. Immunostaining for KIT is frequently lacking (Medeiros 2004). In most cases, codons 842-849 of exon 18 are interested, with the D842V substitution. This mutation has a predictive value, because so far it has proven insensitive to targeted drugs such as Imatinib and Sunitinib. On the contrary, other mutations of PDGFRA are apparently sensitive to Imatinib. On the other side, the prognosis of PDGFRA mutants is more favourable than KIT exon 11 and 9 mutants.
BRAF mutations has been reported in approximately 2% of cases (Hostein 2010). A proportion of GIST, around 10-15%, lack any known mutation. They are referred to as “wild-type” (WT), and are predominant in patients with NF-1, Carney triad and Carney-Stratakis syndromes. Recently it has been shown that a subset of WT-GIST are characterized by deficiency of succinate dehydrogenase (SDH). Whereas in patients with Carney triad no mutations are found, patients with Carney- Stratakis syndromes carry mutations in SDH complex (Wagner 2012; Italiano 2012).

2.2 Histology

2.2.1 Histological features

GISTs display variable morphology (Miettinen 2006; Corless 2011): spindle-cell type in 70% of cases, epithelioid type in 20%, and a mixed pattern in the others. The spindle cells usually arrange themselves in short fascicles of whorls, whereas epithelioid lesions often show a nested architecture. Some lesions are accompanied by a prominent myxoid stroma, collagen deposition and/or interstitial hemorrhages. Nuclei are uniform, ovoid to round, with vescicular chromatin. Morphology is in part related to mutational status, because PDGFRA mutants are more often epithelioid, while KIT exon 11 and 9 mutants are more often spindle-cell. A minority of the tumours show considerable cellular pleomorphism. Recently abrupt transition to high grade morphology has been reported in rare cases, and the term “dedifferentiated GIST” has been suggested to describe this phenomenon (Antonescu 2013). Pediatric type (often SDH deficient) GIST are also characterized by a peculiar morphology that includes multinodularity, infiltrative growth pattern, epithelioid cell morphology, and lymph node metastasis (Rink 2009; Rege 2011).

2.2.2 Immunohistochemistry

GISTs are typically positive for CD117 and DOG-1 (Kang 2010; Novelli 2010). KIT (CD117) is positive in >90% of GIST. CD117 stain is in general strong, diffuse cytoplasmic, or cytoplasmic and membranous, and often involves >90% of tumour cells. A minority of tumours show focal stain or areas with cytoplasmic dot-like stain. These patterns may be related to the mutational status, with, say, PDGFRA-mutated GIST frequently staining negatively. However, it is important to recall that KIT expression (CD117 positivity) does not reflect KIT mutations. It should also be emphasized that CD117 is not GIST-specific, and that several other tumour types may be CD117 positive. However, leiomyosarcomas and malignant peripheral nerve sheath tumours of the gastrointestinal tract, which represent the main differential diagnosis, are usually negative. Therefore, CD117 overexpression is exceedingly useful as a diagnostic tool, although only the mutational status imply a predictive and prognostic value. Molecular biology findings may also be useful diagnostically, in doubtful cases. GIST may be positive for vimentin (>90 %), CD34 (60%), actin (30%), and S-100 protein (10%), while desmin is only rarely positive. DOG1 positivity is observed in approximately 50% of CD117 negative cases. Abolition in SDHB immunoreactivity defines SDH-deficient GIST. Abolition of SDHA immunoreactivity predicts the presence of SDHA mutations (Wagner 2012).

2.3 Accuracy and reliability of pathological diagnosis

2.3.1 Differential diagnosis

There is consensus that CD117 and DOG1 immunostaining should always be carried out because of its frequent positivity in these tumours. On the other hand, CD117 positivity is not sufficient by itself for a pathologic diagnosis of GIST, since other tumours (such as melanoma and seminoma) are positive as well. However, smooth muscle tumours and neural neoplasms of the gastrointestinal tract, which represent the main differential diagnosis of GIST, are usually CD117/DOG1 negative. The differential diagnosis also includes a variety of epithelial, neuroendocrine and melanocytic neoplasms, as well as intra-abdominal fibromatosis (desmoid tumour). Mutational analysis may be of help in doubtful cases, in addition to having predictive value.

3. DIAGNOSIS

3.1 Signs and symptoms

3.1.1 Early diagnosis

A number of GIST are diagnosed incidentally. Logically, some of them will represent an early stage of lesions due to grow subsequently. Most likely, these will be a small fraction of the total, all the more if one takes into consideration also the carefully searched microscopic lesions, whose number might be impressive (Agaimy 2007; Kawanowa 2006). In other terms, a substantial number of GIST may be diagnosed incidentally when they are small, but their clinical meaning is probably negligible in most cases. A watch-and-wait policy may be appropriate for small gastric lesions found incidentally on endoscopy. With regard to clinically relevant lesions, they are often diagnosed at a relatively advanced stage, due to the natural history of these tumours, which tend to give rise to abdominal masses, rather then intraluminal gastrointestinal growings (which would cause early bleeding and/or obstructive symptoms, and thus allow an early diagnosis). Thus, patient may seek medical advice due to symptoms from an abdominal mass, giving rise to abdominal pain and discomfort, or diagnosed incidentally. Sometimes, sideropenic anemia may be the clue to diagnosis. Not infrequently, the first symptoms come at a later stage, and are represented by gastrointestinal or peritoneal bleeding, resulting in an emergency laparotomy with the unexpected finding of a ruptured gastrointestinal mass or a haemorrhagic gastrointestinal neoplasm. This may affect one third of presentations (Scarpa 2008).

3.2 Diagnostic strategy

3.2.1 Instrumental assessment

In gastric, or in the rarer colorectal or oesophageal GISTs, endoscopy may disclose a wall lesion, sometimes ulcerating the mucosa, more often without any superficial infiltration. Thus, endoscopy may be diagnostic in selected cases, but can often be uninformative or of limited value. Endoscopic ultrasound may be required to detect the lesion. More often, CT scan or MRI are able to disclose an abdominal mass, whose origin from the gut wall may be evident or not. Sometimes, even the surgeon at laparotomy may find it difficult to appreciate that the tumour origins from the gut wall. The additional diagnostic value of CT scan and MRI is that they assess whether the disease has spread to the peritoneum and/or to the liver, which are the two main spreading patterns of the advanced disease. Thus, an instrumental abdominal assessment, through CT scan or MRI, is recommended, on a type R basis, in the work-up of suspect GIST. Endoscopy may be useful to detect whether there is mucosal involvement and possibly to allow a diagnostic biopsy. More often, biopsy needs to be performed from the outside, under CT or ultrasound guidance. Preoperative histologic definition of lesions suspected to be GIST helps to properly plan surgical treatment, and all the more allows preoperative medical therapy in those cases in which cytoreduction may allow the surgeon to be more conservative and/or to reduce risks of tumour rupture.

4. STAGING

4.1 Stage classification

4.1.1 Criteria for stage assessment

At the moment, there is no useful stage classification system for GIST. Their origin from the external layers of the gastrointestinal wall, as well as their tendency not to involve regional lymph nodes, make available stage classifications for gastrointestinal malignancies inappropriate. The same is true of stage classifications for soft tissue sarcomas, which are based on the malignancy grade (a true malignancy grading system is unavailable for GIST). By and large, in GIST the equivalent to stages I-III of other neoplasms may be assumed to be the operable localised disease, and the equivalent to stage IV is represented by the metastatic disease to the peritoneum, liver, or, exceptionally, other distant sites. Lymph node extent is infrequent, with the exception of WT GIST.

4.1.2 Localised disease stages

The mitotic rate, tumour size and the tumour primary site are prognostic factors. Some risk assessment systems have been proposed in recent years based on these factors. A risk partitioning based on a large retrospective analysis with long-term follow-up is available (Miettinen 2006). A nomogram is available (Gold 2009), as well as a risk classification updating the previous 2002 NIH system (Joensuu 2008). The main limitation of these systems is that mitotic count and tumour size are dichotomous variables, so that large variations in prognosis are apparent for small changes in their values. Prognostic contour maps have been proposed, using mitotic count and tumour size as continuous variables, in addition to tumour site and tumour rupture (Joensuu 2012). In fact, tumour rupture confers a dismal prognosis, independent on the other prognostic factors (Hohenberger 2010).

4.1.3 Disseminated disease stage

GIST tend to metastatize to the peritoneum and to the liver, so that the disease tends to remain confined to the abdomen throughout its natural history. Extra-abdominal metastases may occur in a limited proportion of patients, mainly to bones. Supradiaphragmatic nodes, and distant soft tissues may be rarely affected. Lung lesions are rare, with the exception of rectal GIST.

4.2 Staging procedures

4.2.1 Assessment

CT scan or MRI are needed to document the extent of the tumour and whether peritoneal and/or liver spread is present. Endoscopy helps detect mucosal involvement. Lung lesions are infrequent, but a CT scan, also exploring mediastinal nodes, is added to the initial staging workup. Other assessments are practically useless, in the absence of symptoms pointing to very rare sites of metastases.

5. PROGNOSIS

5.1 Natural history

5.1.1 Risk of recurrence

Very small lesions, with a very low mitotic rate, incidentally found during manoeuvres carried out for other reasons, have a favourable prognosis. If one considers all patients with clinically meaningful disease, roughly 60% of those with local, operable disease are likely to be cured of their disease through surgical excision, but risk of relapse varies widely depending on main prognostic factors, i.e., include mitotic rate, tumour size, and primary site. They help break down this patient population into widely differing risk categories (Miettinen 2006; Joensuu 2012). Mitotic rate should be ideally evaluated as continuous variables (Rossi 2011; Joensuu 2012).

5.1.2 Local disease

GIST arise from within the gastrointestinal wall. A few cases might be extragastrointestinal, originating from the mesentery and omentum, but occult gastrointestinal disease may be present in these cases either. Around 60% of GIST arise from the stomach, 30% from the small bowel, 5-10% from rectum (rarely from colon), <5% from oesophagus.

5.1.3 Metastatic disease

A proportion of GIST which may exceed 15% are diagnosed when they are already metastatic. Otherwise, metastases may be found following local treatment, often within 2-3 years from surgery. Late relapses may occur, however, especially when the initial mitotic rate is low. Typically, the advanced disease implies spreading of lesions throughout the peritoneum and/or the liver. By and large, 50% of metastatic patients will have both liver and peritoneal spread, 35% only peritoneal disease, and 15% only liver lesions. Peritoneal spread results in small to great masses scattered throughout the abdominal cavity. Of course, they may result in signs of intestinal obstruction, urinary compression, and pain. Liver nodules may be more or less in number, but can result in huge organ involvement. Before the introduction of Imatinib, overall median survival in the advanced disease was in the 1-2 year range for patients with isolated liver metastases and one year for patients with peritoneal spread. Cases of relatively long survival, in terms of some years, after the outset of the advanced phase of disease, were reported and are likely to have been wild-type GIST. Bone lesions may occur, mainly in the presence of abdominal metastases with a history of treatment with targeted agents. Rare sites of metastases are distant lymph nodes (e.g., in the mediastinum), subcutaneous tissues, lungs. Metastases to these sites are very rare, however. Lung metastases, in particular, are very rare, in sharp contrast to sarcomas, with the exception of rectal GIST.

5.2 Prognostic factors

5.2.1 Mitotic count

Currently, mitotic count is the most important pathologic predictor of recurrence. It is generally felt that 5-10 mitoses per 50HPF may serve as a threshold to distinguish a low from a high risk subgroup of patients. Possibly, this threshold might vary a little depending on the anatomic site of origin of the disease. In general, however, mitotic count should be viewed as a continuous prognostic variable.

5.2.2 Size

Tumour size at presentation is a strong predictor of recurrence. While lesions with a diameter <2 cm and a low mitotic rate are considered to be very low risk, lesions in excess of 5-10 cm imply a high risk of recurrence.

5.2.3 Site of origin

In regard to the most frequent sites of origin, gastric GISTs are associated to a better prognosis than small bowel and rectal ones. The rare oesophageal, duodenal, and extragastrointestinal GISTs entail a less favourable prognosis.

5.2.4 Others

Tumour rupture is a highly adverse prognostic factor, and some clinicians consider it almost equal to peritoneal dissemination (Rutkowski 2011). Mutational status is a prognostic factor, though the independent correlation of single mutations with prognosis may be difficult. However, there is no doubt that the prognosis of PDGFRA-mutated GIST is better than KIT-mutated. In addition, the natural history of WT GIST is different and overall more indolent than KIT-mutated GIST.

5.3 Predictive factors

5.3.1 CD117

CD117 is neither a prognostic nor a predictive factor.

5.3.2 Mutational status

Mutations to KIT exon 11 are more responsive to Imatinib than mutations to KIT exon 9, which however take benefit from higher doses of the drug, as well as Sunitinib (Corless 2011). KIT exon 13 and 17 are responsive. PDGFRA mutations are often of the D842V type, and are known to be insensitive to both Imatinib and Sunitinib. Other PDGFRA mutations are sensitive. WT GIST are less sensitive to Imatinib than KIT- and PDGFRA-mutated GIST, though they may respond to Sunitinib and other agents.

6. TREATMENT

6.1 Local disease

6.1.0 Overall treatment strategy

Surgery is the treatment mainstay for localised disease, i.e. those presentations in which complete excision of the primary tumour is feasible and the disease has not spread elsewhere. While 50-60% of patients are thereby cured, the proportion is higher for some subsets and lower for others depending on the mitotic count, tumour size and tumour site (DeMatteo 2000; Miettinen 2006; Joensuu 2012). Thus, complete surgical excision is standard treatment for local disease, on a type C basis. Adjuvant therapy with Imatinib for 3 years was shown to result in a substantial prolongation of relapse-free interval in comparison to 1 year of the same adjuvant treatment, with a limited survival advantage, in the high-risk subset. Previously, a placebo-controlled randomized trial showed that adjuvant Imatinib for 1 year was superior to no further treatment after surgery in GIST with a tumour diameter >1 cm (DeMatteo 2009; Joensuu 2012). Thus adjuvant Imatinib for 3 years is standard treatment for patients with a high risk of relapse, on a type 1 evidence. It is recommended to reserve adjuvant treatment to potentially sensitive genotypes, on a type R basis, though there is not a universal consensus on sparing adjuvant therapy to WT GIST. When surgery can be made more conservative, or safer, in the case of a tumour response, primary pre-surgical (neoadjuvant) therapy with Imatinib is ordinarily used, though in the lack of controlled evidence (Eisenberg 2009; Fiore 2009; Jakob 2013). Thus it should be considered suitable for individual clinical use in selected cases, on a type R basis.

6.1.1 Surgery

A complete R0 excision of the tumour is the standard surgical option for operable localized GISTs, on a type C basis. It is left to determine how critical a R1 residual may be for the long-term outcome (DeMatteo 2000). It is logical to perform complete surgery, with no microscopic residual, in all cases in which this is feasible. In the case of R1 residual disease following already performed surgery, it is uncertain whether re-excisions may be worthwhile. It seems reasonable to base these decisions on an overall prognostic assessment, as well as on the kind of microscopic residual one is dealing with (actual intralesional surgery, surgical marginality, contamination) and how much this can be salvaged in principle by re-excision or more extensive surgery. Surgery should avoid any tumour rupture because this was proven to be a highly adverse prognostic factor (Hohenberger 2010; Rutkowski 2011). Preoperative Imatinib may be resorted to in an effort to increase the safety of planned surgery.

6.1.2 Adjuvant therapy

A randomized clinical trial showed that Imatinib 400 mg daily for 1 year gives a benefit in relapse-free survival versus placebo (DeMatteo 2009). An additional trial showed that Imatinib 400 mg daily for 3 years provides a higher benefit than if given for 1 year in terms of relapse-free survival and overall survival (Joensuu 2012). The first trial accrued all GIST patients with a tumour size higher than 3 cm, and the benefit was shown to be related to the prognosis of patients, since a subgroup of these patients had a very low risk of relapsing. The second trial enrolled patients with a high-risk GIST. Only preliminary data are available as to the differential efficacy of adjuvant Imatinib across genotypes, but it is widely felt that an insensitive mutation such as the PDGFRA D842V is at least very unlikely to take any benefit. This may well apply also to WT GIST, and the natural history of these tumours is more indolent, so that in many centers these patients do not receive adjuvant therapy, though in the lack of a general consensus about this. Relapse-free curves tend to overlap again after 2-3 years from the end of adjuvant therapy, so that one could believe that continuing adjuvant therapy beyond 3 years may pay off. However, results are not available at the moment for longer adjuvant intervals. The main concern is that it is unknown whether this may result into earlier emergence of resistance, and patients relapsing after the end of adjuvant therapy are due to receive Imatinib as their standard treatment. This is the reason why Imatinib can be regarded as standard treatment for 3 years on a type 1 basis in high-risk GIST patients with a potentially sensitive mutational status. No results are available as to the efficacy of 400 versus 800 mg daily of Imatinib in the adjuvant therapy of GIST patients with an exon 9 KIT mutation, since a dose of 800 mg was shown to be of higher efficacy in this subgroup in the metastatic setting, but no study was undertaken in the adjuvant setting focusing on the best dose in exon 9 KIT-mutated patients (MetaGIST 2010).

6.2 Disseminated disease

6.2.0 Overall strategy

The approach to the metastatic disease is based on molecularly targeted therapy with Imatinib mesylate, which is standard treatment, on a type C basis (Demetri 2002; Verweij 2004; Blanke 2008) in untreated patients and in those who received adjuvant Imatinib without developing a relapse while this was ongoing. Therapy must be continued indefinitely, since the disease progresses if therapy is stopped, even in those cases in which a radiological complete remission is achieved (Le Cesne 2010; Patrikidou 2013). The limiting factor of Imatinib is secondary resistance, after which Sunitinib is standard therapy as a second-line therapy, on a type 1 basis (Demetri 2006). After failure to Sunitinib, Regorafenib is standard therapy, on a type 1 basis (Demetri 2013). Before switching from Imatinib to an alternative drug, one should check that there are no pharmacokinetic problems which may diminish the efficacy of the administered dose of the drug. In any case, an attempt to escalate Imatinib dosage to 800 mg is generally made (Zalcberg 2005). In addition, in case of focal progression (progressive disease limited to one lesion, while the others continue to respond), surgery of progressing lesion or ablative techniques are suitable for individual clinical use on a type 3 basis (Raut 2010). On the contrary, surgery of generalised progression was shown to be unfruitful. Surgery of responding disease has been associated to improved outcome in retrospective case series analyses, with the rationale of contributing to avoid, or delay, secondary resistance. No prospective demonstration thereof has been provided, however. Given the possibility of selection biases, in the lack of prospective controlled evidence, surgery of residual disease is therefore suitable for individual clinical use, on a type 3 basis, generally after 6-12 months from starting Imatinib, i.e., when maximum tumour response has developed. Imatinib is selected in case of sensitive mutations (affecting KIT and PDGFRA, with the exception of D842V), but may work also in some wild-type GIST, while PDGFRA D842V mutations are insensitive. In case of an exon 9 KIT mutation, there is evidence from subgroup analyses that a daily dose of 800 mg is superior to 400 mg in terms of progression-free survival (MetaGIST 2010). Wild-type GIST may respond to Sunitinib.

6.2.1 Medical therapy

Imatinib mesylate: Imatinib is an inhibitor of the KIT tyrosine kinase. Currently, therapy is started at 400 mg and given on a daily basis. Two large randomized trials comparing 400 mg versus 800 mg daily showed that there is not a difference between the two dose levels (Verweij 2004; Blanke 2008). However, an unplanned analysis of the subgroup with an exon 9 KIT mutation made by combining the two studies showed that these patients had a better progression-free survival if given 800 mg (MetaGIST 2010). Likewise, a cross-over mechanism was foreseen in the two trials, which showed that escalating the dose to 800 after progressing to 400 mg implied a short-term benefit for a proportion of these patients (Zalcberg 2005). Thus, it is currently recommended, on a type R level of evidence, to start Imatinib 400 mg daily, and then escalate to 800 mg in case of progression or unresponsiveness. Retrospective data have been provided that plasma levels of Imatinib in excess of 1,100 ng/mL were associated with a better prognosis (Demetri 2009). However, no prospective evidence has been provided, so that a selection bias cannot be ruled out. In addition, the best way to assess pharmacokinetics is undefined currently. On the other hand, pharmacokinetics variations have been recorded over time, so that the practice of escalating Imatinib’s dose in case of progression to 400 mg may be logical all the more. Studies are needed to learn how to incorporate pharmacokinetics assessments within a patient tailored drug management for Imatinib as well as, probably, all the other oral agents used in subsequent treatment lines. More common toxicities include peripheral oedema, bowel movements, skin rash, fatigue, minor myelosuppression and liver toxicity. In <5% of patients, major bleeding within tumour lesions, due to tumour response, may follow treatment start, and occasionally pose serious risks (e.g., gastrointestinal bleeding, sudden anemia, perforations). Patients should be therefore monitored for occult bleeding in the early phase of therapy. Surgery might be required in exceptional cases. Tumour response may be exceedingly rapid also from a biomolecular perspective, and this may be disclosed by PET scan, which may become negative very soon after treatment start. On the contrary, assessment of tumour response through CT scan or MRI may be made difficult in some cases by intratumour hemorrhage, or, more often, by tissue alterations possibly leaving tumour volume unaltered for a relatively long time or even enlarging it for a while. Thus, a simil-cystic appearance of lesions (being markedly hypodense) point to a tumour response even in the presence of some enlargement in their volume (Choi 2007; Van den Abbeele 2008). Tumour changes in resected patients have proven consistent with a myxohyaline degeneration, with a varying residual population of tumour cells, from scattered apoptotic figures to apparently vital cells (Hohenberger 2010). Secondary resistance is the limiting factor of therapy with Imatinib in the metastatic setting. Its median time of occurrence from starting Imatinib therapy was in the 2-yr range in clinical trials, though this interval is sensitive to the tumour burden at the beginning of therapy, so that one may expect that today it is better given the earlier diagnosis of relapse in comparison to patients accrued in first trials on Imatinib in the advanced disease setting. As a matter of fact, a proportion of long-term progression-free survivors (>10 years) was found in those trials, apparently in the 10% range (Casali 2013). It is left to understand which prognostic factors may identify this patient subset. The main conceptual limitation of secondary resistance is its policlonality, by which, for example, biopsies of several lesions in the same patient may turn out to show different mutations (Wardelmann 2006). Of course this is a major difficulty for the efficacy of further-line therapies based on agents with a mechanism of action close to Imatinib. This is the reason why clinical studies are open on agents with a different mechanism of action, or combinations of different agents.
Sunitinib: Sunitinib is an inhibitor of KIT and PDGFRA as well as an antiangiogenic agent. It was shown to result in a median benefit of 5 months in progression-free survival in a randomized placebo-controlled trial in patients progressing on, or intolerant to, Imatinib (Demetri 2006). Main toxicities were fatigue, hand-foot skin syndrome, diarrhoea and nausea. Sunitnib was administered according to a 4 week on / 2 week off schedule. A continuous regimen with a lower daily dose was shown effective in a uncontrolled study (George 2009).
Regorafenib: Regorafenib is an inhibitor of KIT and PDGFRA as well as an antiangiogenic agent. It was shown to result in a median benefit of 4 months in progression-free survival in a randomized placebo-controlled trial in patients progressing on, or intolerant to, Sunitinib (Demetri 2013). Main toxicities were hypertension, hand-foot skin syndrome and diarrhoea.
Rechallenge: There is evidence from anecdotal reports and also a small Phase 3 trial that rechallenging the same patient with agents to which he developed progression results into a further progression free survival benefit (Blay 2012; Kang 2013). Furthermore, the feeling is that maintaining the tyrosine kinase inhibition, even in case of progression, may pay off to some extent, when of course alternative drugs are not available or rechallenge with drugs used previously is unfeasible (Casali ESMO 2012).

6.2.2 Surgery

If resorted to, surgery of residual disease during medical therapy with Imatinib should be viewed as a debulking surgery, aimed at excising gross residual disease in an attempt to delay secondary resistance. The efficacy thereof has not been demonstrated prospectively, since a selection bias cannot be ruled out for available retrospective series pointing to a better outcome for surgically treated patients in response to Imatinib. All the more this is true for patients responding to further-line therapies (Raut 2010, Mussi 2010). Debulking surgery in non responsive patients to Imatinib was shown to be ineffective. However, a limited progression-free survival gain may be achieved through surgery of focally progressing disease, so that this is largely resorted to currently. Emergency surgery may be required, due to bleeding caused by response to Imatinib, especially, but not only, in the early stages of therapy, or following other complications, including infections due to perforations, and the like.

7. LATE SEQUELAE

7.1 Treatment late effects

7.1.1 Surgery

Late sequelae of surgery for GISTs may be superimposable to those of surgery for gastrointestinal cancer. Total gastrectomy may be needed in gastric GIST. Sphincter-saving surgery may be unfeasible in rectal GIST.

7.1.2 Medical therapy

Over late effects from Imatinib are currently held to be limited, though data may still be lacking

8. FOLLOW-UP

8.1 Principles and objectives

8.1.1 Local disease

Roughly 80% of recurring GIST patients do so within 2-3 years from surgery for local disease, even if long delayed recurrences are well known. In addition, 95% of recurrences selectively involve one or both the typical sites of relapse in this disease: peritoneum and liver. Abdominal CT-scan or MRI are thus of choice to detect most frequent recurrences from GIST. Possibly, they might be alternated to ultrasounds, especially in thin patients. Risk of recurrence is essentially dictated by mitotic count, size, and site of origin. High-risk patients are generally kept into close follow-up for recurring disease to the abdomen, at least in the early years from surgery. Then, follow-up intervals may be relaxed, though long-term monitoring is advisable. Low risk patients may benefit from slightly relaxed controls, but the time interval at risk for relapse may indeed be prolonged. Adjuvant therapy is able to delay relapses, whose probability increases as from 1-2 years from its end, and this should be factored in follow-up policies.

8.1.2 Disseminated disease

GIST patients in response on Imatinib deserve to be strictly watched because the risk of secondary resistance increases over time.

8.2 Suggested protocols

8.2.1 Local disease

Regular follow-up with CT scan or MRI, possibly alternating with ultrasounds in thin patients, at close intervals, is recommended, on a type R basis, at least in the first years, especially in high risk patients. Then intervals can be relaxed, but follow-up should be prolonged for several years. A reasonable protocol may include abdominal CT or MRI every 3 months for 2 years from surgery, or the end of adjuvant therapy, then every 6 months for further 3 years, then yearly.

8.2.2 Disseminated disease

It is recommended, on a type R basis, that patients on therapy with Imatinib and other agents be closely followed-up. Generally, this happens at 3-months intervals or so.

INDEX

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Dr. Rossella Bertulli (Associate Editor)
Istituto Nazionale Tumori – Milan, Italy
mail: rossella.bertulli@istitutotumori.mi.it

Dr. Paolo Bruzzi (Biostatistics editor)
Istituto Nazionale per la Ricerca sul Cancro – Genoa, Italy
mail: paolo.bruzzi@istge.it

Dr. Paolo G. Casali (Editor)
START Clinical Editor – Istituto Nazionale Tumori – Milan, Italy
mail: paolo.casali@istitutotumori.mi.it

Dr. Maurizio Colecchia (Consultant)
Istituto Nazionale Tumori – Milan, Italy
mail: maurizio.colecchia@istitutotumori.mi.it

Dr. Judith Diement (Consultant)
Istituto Nazionale Tumori – Milan, Italy

Dr. Alessandro Gronchi (Consultant)
Istituto Nazionale Tumori – Milan, Italy
mail: alessandro.gronchi@istitutotumori.mi.it

Prof. Juan Rosai (Reviewer)

Dr. Elena Tamborini (Consultant)
Istituto Nazionale Tumori – Milan, Italy
mail: elena.tamborini@istitutotumori.mi.it

Prof. Allan T. van Oosterom (Reviewer)
UZ Ku Leuven – Leuven, Belgium
mail: allan.vanoosterom@uz.kuleuven.ac.be