Carcinoid tumors

oncology

1. Carcinoid Tumors

2. D E F I N I T I O N These are slow growing tumors of neuroendocrine system that belongs to amine precursor uptake and decarboxylation (APUD) system. Oberndorfer in 1907 Karzinoid : carcinoma like are thought of arise from enterochromaffin cells , also known as kulchitsky cells.

3. Carcinoid tumours Neuroendocrine tumors - comprise a broad family of tumors, the most common of which are ; carcinoid tumors (most commonly arising in the lungs and bronchi (so-called bronchopulmonary ), small intestine, appendix, rectum, and thymus) and pancreatic neuroendocrine tumors. Other less common neuroendocrine tumors include those arising in the parathyroid, thyroid, adrenal, and pituitary glands).

4. The SEER database estimated that the incidence of neuroendocrine tumors in the United States was 5.25 cases per 100,000 people in the year 2004. True Incidence and Prevalence of NETs Most Likely Underestimated. Approx 2/3 rd of carcinoid tumours arise in GIT and 1/3 rd in lungs or thymus. Carcinoids are the Second Most Prevalent Type of GI Malignancy.

5. Sporadic or inherited genetic syndromes.

6. Carcinoid tumors are composed of monotonous sheets of small round cells with uniform nuclei and cytoplasm, and mitotic figures are rare. Pathologists cannot differentiate benign from malignant carcinoid tumors based on histologic analysis. Malignancy can only be determined if there is invasion or distant metastases

7. Site of origin NETs are generally classified as foregut, midgut , or hindgut depending on their embryonic origin . Foregut • Thymus • Esophagus • Lung • Stomach •Duodenum Pancreas Midgut • Appendix • small bowel • Cecum • Ascending colon Hindgut • Distal large bowel • Rectum

8. Classification of Carcinoid Tumors HISTOCHEMISTRY Foregut Midgut Hindgut Silver staining Argentaffin – argyrophilic + Argentaffin + argyrophilic + Argentaffin – argyrophilic + Chromogranin -A & Neuron-specific enolase Positive Positive Positive PRODUCTS Tumor Low 5-HT content, High 5-HT content, Rarely 5-HT. Blood 5-HTP ,histamine, multihormonal occasionally secrete ACTH 5-HT , multihormonal , rarely secrete ACTH Rarely release 5-HTP or ACTH Carcinoid syndrome Occurs but may be atypical Occurs frequently -Typical (with metastases) Rarely occurs Metastasize to bone Common Rarely Common

9. Histologic Classification Neuroendocrine tumors are classified histologically based on tumor differentiation (well or poorly differentiated) and tumor grade (grades 1–3). Most neuroendocrine tumors fall into 3 broad histologic categories: - well-differentiated, low-grade (G1); - well-differentiated, intermediate-grade (G2); and - poorly differentiated, high-grade (G3).

10. Grading Of NET ( european NET society/WHO) Low grade Intermediate grade High grade Typical carcinoid Mitotic count (10HPF):<2 Ki-67 index: </= 2 Atypical carcinoid Ki67 is most often positive. Mitotic count (10HPF): 2-20 Ki-67 index: 3-20 Small cell carcinoma Large cell neuroendocrine carcinoma Mitotic count (10HPF): >20 Ki-67 index:>20

11. Grade is generally defined by mitotic count and/or Ki-67 index, whichever is higher. In some cases, however, tumors may not fall clearly into one category. For example, a morphologically well- differentiated neuroendocrine tumor with a low mitotic index may have a Ki-67 proliferation index that falls into the high-grade category. While technically classified as a high-grade tumor, clinical judgment should be used in making treatment decisions for such cases The classification of lung and thymus carcinoids - does not include Ki-67 and includes the assessment of necrosis.

12. TNM staging 7 th edn , 2010 STOMACH, DUODENUM, JEJUNUM,ILEUM AMPULLA COLON, RECUM APPENDIX T1 Lamina propria / submucosa & </= 1Cm </= 1Cm T1a:<1cm T1b:1- 2 cms T1a:</=1cm T1b:>1- 2 cms T2 Muscularis propria or >1cm >1cm Muscularis propria or >2cm >2 to </= 4cms T3 subserosa Invades pancreas or RP or non peritonalised tissue Subserosa or non peritonalised pericolic & perirectal tissues > 4cms or extension to ileum T4 serosal Invade other organs Peritonium & other organs Other strs , abdo wall & skeletal muscle

13. No/N1; Mo/M1 Staging Stage 0 -Tis No Mo Stage I -T1 No Mo Stage IIa -T2 No Mo Stage IIb -T3 No Mo Stage IIIa -T4 No Mo Stage IIIb - anyT N1 Mo Stage IV - anyT anyN M1

14. CLINICAL FEATURES MIDGUT Usually incidental Periodic abdominal pain (51%) Intestinal obstruction with ileus (34%) Abdominal tumor (17%) GI bleeding 1% Features of acute appendicitis Hepatomegaly

15. CLINICAL FEATURES RECTAL Bleeding Constipation Diarrhoea BRONCHIAL Pneumonia Hemoptysis Cough

16. CLINICAL FEATURES Systemic symptoms are consequences of the peptide released by the tumor Carcinoid syndrome Cushing’s Syndrome Acromegaly Peptic ulcer disease Heart problem

17. Specific markers for carcinoid tumors Biochemical markers: often elevated in NETs and can be a surrogate marker of symptoms of hormone excess or tumor growth. Chromogranin A levels are elevated in approximately 80% of patients with GI NETs; - sensitivity is 75% and specificity 85%. - Falsely positive elevated -PPI or H2 receptor antagonist, hepatic or renal failure. Urine 5-hydroxyindoleacetic acid (5-HIAA) , the primary metabolite of serotonin, is elevated in carcinoid syndrome. --- - Sensitivity of 35% and specificity of 100%. - Abnormal levels (>5 mg/24 hours) of 5-HIAA are diagnostic of carcinoid syndrome. - to avoid false positive results -avoid some diet & medication s. ACTH

18. Systematic Approach to Diagnosing NETs GI Endoscopy Bronchoscopy CT scan/ MRI PET scan

19. Endoscopy: Gastric and rectal carcinoids are often asymptomatic and are thus most commonly imaged on screening or diagnostic endoscopy. Endoscopic ultrasound has aided in the characterization of these tumors.

20. CT scan Primary tumor localization is rare with CT because of its submucosal location and often small size CT is effective at identifying the mesenteric stranding/fibrosis that often accompanies carcinoid tumors, as well as mesenteric nodal involvement The desmoplastic response can also cause changes in the mesenteric vasculature that can be identified with CT-angiography CT is most effective for identifying hepatic metastasis, with sensitivity greater than 85% Metastatic carcinoid tumors are highly vascular and hence display bright enhancement during arterial-phase imaging The role of magnetic resonance imaging (MRI) in the diagnosis of a primary carcinoid tumor is limited, and it adds little or no information above that provided by CT

21. SRS has been used to image carcinoid tumors. Most NETs express somatostatin receptors that can bind and internalize the currently available octapeptide somatostatin analogues octreotide and lanreotide . This feature can be exploited both in terms of somatostatin receptor-based treatments and scintrigraphy (SRS). -Based on  111In-labeled diethylenetriamine pentaacetic acid (DPTA ) Octreoscan . 80% to 90% sensitivity and specificity in identifying carcinoid neoplasms The technology is also limited in patients who do not exhibit carcinoid syndrome, for whom the sensitivity is only 60% for identification of the primary tumor

22. PET has had mixed results in imaging carcinoid tumors FDG-PET appears to be sensitive and specific in identifying carcinoid tumors that exhibit high proliferative activity or are poorly differentiated. ( PET) scanning with Ga-68 DOTATATE is a newer somatostatin -based scintrigraphy that is thought to be more sensitive than 111In scans. 131I-metaiodobenzylguanidine (MIBG) scans – limited studies have shown results roughly equivalent to those of CT, with a sensitivity of 55% to 85% and a specificity of 95% especially helpful in patients who are being maintained on long-term octreotide therapy or whose tumors secrete catecholamines . CT- enteroclysis a newer imaging modality designed to image tumors of the small bowel. It has a sensitivity of 86% and a specificity of 100% for small bowel NETs.. Echocardiography is also included in the diagnostic workup to either confirm or exclude carcinoid heart disease.

23.  Magnetic resonance image showing a single focus of metastatic disease  (arrow)  in the right lobe of the liver in a patient with a carcinoid tumor and elevated 5-hydroxyindoleacetic acid.  B,  A 111In-labeled pentetreotide scan of the same patient shows multiple hepatic lesions and two involved para-aortic lymph nodes.

24. General Management Principles Management of NETs falls under two main categories: 1) Therapies directed at tumor control and 2) Therapies directed at controlling symptoms of hormone excess.

25. General Management Principles Surgical resection remains the mainstay of treatment for resectable NETs of the GI tract and lungs. In addition to prolonged survival, surgery can also palliate symptoms of obstruction, diarrhea , flushing,and /or pain with eating . In the setting of unresectable disease, antitumor therapy is only indicated in the setting of symptoms, tumor bulk, and/or disease progression. In newly diagnosed asymptomatic patients with unresectable or metastatic disease, it is often reasonable to monitor closely without any active treatment.

26. MANAGEMENT BY PRIMARY TUMOR SITE Esophageal Neuroendocrine Tumors very uncommon (<1% of GI NETs ) distal esophagus just proximal to the esophageal-gastric junction Endoscopic ultrasonography and SRS are indicated for staging because lymph node metastases occur in 50% of patients . Endoscopic mucosal resection (EMR) is done if there is no evidence of lymph node metastases and the tumor is amenable to complete excision . - Open resection is done for patients with lymph node metastases. The operative procedure is most commonly an Ivor Lewis esophagogastrectomy .

27. GASTRIC CARCINOIDS 9% of GI NETs , arise from the enterochromaffin -like (ECL) cells of the stomach that occur in the gastric fundus and body 3/1000 gastric neoplasms 3 Types- Type I - Atrophic gastritis Type II – ZES Type III – No hypergastrinemias Hypergastinemia

28. Gastric carcinoid tumors- Three subtypes Two subtypes are associated with hypergastrinemic states, either Chronic atrophic gastritis (type I; 80%) or Zollinger -Ellison syndrome (type II; 6%), almost always as part of MEN-1,--there is allelic loss at the MEN-1 locus on chromosome band 11q13, and thus fundic gastric carcinoid tumors are now included in the spectrum of MEN-1 tumors. These tumors generally pursue a benign course, with 9% to 30% LN metastases, distant mets 10-20% usually multicentric and small, with infiltration restricted to the mucosa and submucosa , size- few mm to 1.5 cm

29. Gastric carcinoid tumors- cont.., The third type of gastric carcinoid Type III-(15-20%) -sporadic ECL tumors occurs without hypergastrinemia , - often large (mean size 3 cm) & solitary, - pursue a more aggressive course, - Most lesions invade the full thickness wall of the stomach. - located in the body or fundus. - Regional lymph node and liver metastases in 70% of patients - 50% have atypical histologic features, and some patients develop carcinoid syndrome.

30. Site specific mang of Gastric carcinoid Loco regional disease

31. <4% of all GI NETs more common in the proximal duodenum usually small <5 mm (30% to 70%) spread to regional LNs such that adjacent lymph node sampling is recommended not commonly spread to distant sites In contrast to jejunoileal carcinoid tumors, duodenal carcinoid tumors are often discovered by endoscopy. Duodenal carcinoid tumours

32. Site specific mang of carcinoid tumour SmalI intestine

33. Small intestinal carcinoid tumors Small bowel NETs are most common , 42% of all GI NETs, and they are most prevalent in ileum within 20 cm of the ileal-cecal valve . Ileal NETs are commonly very small (2 to 4 mm) and multiple within the wall of the ileum, with adjacent large lymph node metastases that cause cicatrization and venous conjestion that can result in small bowel obstruction . Approximately 50% of patients will have liver metastases or peritoneal carcinomatosis at the time of diagnosis. Cholecystectomy is also indicated because most of these patients with either lymph node or liver metastases will require the longterm use of somatostatin analogues that can cause gallstones when administered long-term.

34. Appendiceal carcinoid Tumors In the past carcinoid tumors were most frequently reported in the appendix (approximately 40%); however, more recently small intestine and the bronchus & lung are the most common sites A carcinoid tumor is discovered in approx one out of every 200 to 300 appendectomies. - Most occur in the tip of the appendix. - The majority (i.e., 90%) are less than 1 cm in diameter without metastases

35. Site specific mang of carcinoid tumour

36. Colonrectal carcinoid Tumors 4% of GI NETs and 1% to 5% of colorectal tumors. Mc site Rt colon majority of colon NETs are well differentiated but some are large, less differentiated, and exophytic and have a higher incidence of lymph node and liver metastases. The 5-year survival for colon NETs is 37%, Rectal carcinoid Tumors 27% of GI NETs and 1% to 2% of all rectal tumors

37. Carcinoid Syndrome Malignant carcinoid syndrome is a clinical entity marked by flushing, diarrhea, abdominal cramping, wheezing, heart valve dysfunction, and pellagra Flushing (63% -74%) Cardiac disease (14% -41%) Diarrhea (68% -73%) Dermatitis (5 %) Abdominal pain (10% -34%) Bronchoconstriction (3% -18%)

38. It is found in 10% to 18% of all patients with carcinoid tumors, but the incidence increases to 40% to 50% in patients with advanced disease Carcinoid tumors produce a large number of substances, including serotonin, tachykinins , and histamine. It is the actions of serotonin that lead to many of the manifestations of carcinoid syndrome. Develops in the presence of hepatic metastasis, which precludes hepatic inactivation of the active metabolites of serotonin.

39. CARCINOID SYNDROME 91% CASES – Only AFTER DM TO LIVER EXCEPTION Lung carcinoids Ovarian carcinoids Pancreatic carcinoids

40. The development of carcinoid syndrome is related to the embryologic origin of the original tumor TYPICAL CARCINOID SYNDROME - Midgut carcinoids are the most common source of carcinoid syndrome because these tumors produce high levels of serotonin - More than 90% of all patients suffering from carcinoid syndrome have a midgut primary ATYPICAL CARCINOID SYNDROME Foregut carcinoids lack the aromatic amino acid decarboxylase required to convert 5-hydroxytryptamine (5-HT) to serotonin and therefore cannot produce the classic carcinoid syndrome. In patients with gastric carcinoid tumors. secondary to large release of histamine from the tumor rather than serotonin. - Hindgut carcinoids also lack the ability to convert tryptophan to serotonin, and thus even if metastatic lesions are present, carcinoid syndrome will not develop.

41. TREATMENT OF CARCINOID SYNDROME Avoid stress and precipitating factors Diuretics – heart failure Bronchodilators – wheezing Antidiarrhoeal agents, niacin supplementation Somatostatin analogues ( octreotide ) – 100 mg s/c 8 hourly – 3000 mg/ day Before surgery – 150-250 mg s/c 6-8 hrly 24-48 hrs prior to anaesthesia Inhibitors of serotonin synthesis are emerging as a new class of agents to treat carcinoid syndrome. Telotristat etiprate

42. Metastatic Disease Cytoreductice Rxs for metastatic carcinoids Surgery/ local ablative therapy Hepatic artery chemoembolisation Systemic CT

43. Surgical Therapy Approach to the treatment of metastatic disease is based on symptoms. - Resection of the primary site in the setting of unresectable metastases is generally not indicated if the primary site remains asymptomatic and is relatively stable. P atients with limited hepatic metastases or other sites of disease can undergo complete resection of the primary tumor and metastases with curative intent. Noncurative debulking surgery can also be considered in select cases, especially if the patient is symptomatic either from tumor bulk or hormone production -Such resection aids in avoiding complications from growth of the primary tumor in terms of bleeding , obstruction, and abdominal pain, especially with midgut carcinoids because of their propensity to cause intense fibrosing reactions

44. -By using a resection or ablative approach to hepatic metastases, the patient can be palliated and even enjoy a long-term survival benefit. -Surgical therapy for metastatic carcinoid tumors is aimed at removing more than 90% of the tumor burden via either anatomic or wedge resections, with acceptable morbidity and mortality rates of 15% and 1.2%, respectively -By using this cytoreductive approach, symptoms from metastatic carcinoid are reduced in 95% of patients, with a median symptom-free duration of 45 months. - Five-year survival rates improve from 40% to 50% in patients who do not undergo surgery to 60% to 82% in patients after hepatic resection of their metastatic disease

45. Patients whose tumor is unresectable or in whom reduction of greater than 90% of the tumor burden is not feasible Liver directed therapies include (CAT-2B) -radiofrequency ablation (RFA), - cryotherapy , -hepatic arterial occlusion, - embolization , and - chemoembolization . Orthotopic liver transplantation - its true role in the treatment of patients with metastatic carcinoid remains unclear -Patients who appear to have the greatest survival rates are those with well-differentiated tumors that exhibit low proliferative activity -In this select group, orthotopic liver transplantation can yield a 5-year survival rate of up to 69%

46. ANTITUMOR Medical Therapy focused mainly on relief of the symptoms of carcinoid syndrome Somatostatin Analogues -The most commonly used therapy. -The somatostatin receptors are blocked with a somatostatin analogue, thereby relieving the flushing, diarrhea, and other symptoms of carcinoid syndrome. -The most commonly prescribed agent has been octreotide -However , the short half-life of octreotide necessitates continuous infusion or twice-daily subcutaneous injections . -The long-acting release (LAR) formulation of octreotide is commonly used -Standard doses of octreotide LAR are 20 to 30 mg intramuscularly every 4 weeks. -Therapeutic levels are not achieved for 10 to 14 days after LAR injection. Short-acting octreotide (usually 150–250 mcg subcutaneously 3 times daily) - Lanreotide is administered every 10 to 14 days(60 to 120 mg). Side effects of the treatment include sinus bradycardia , arrhythmias, gallbladder stones, steatorrhea , hypothyroidism, and hypoglycemia

47. PROMID - The best clinical evidence came from this trial, - Phase 3 study RCT - 85 patients - Metastatic midgut carcinoids to - Octreotide LAR 30 mg versus placebo. Significant improvement of median time to progression from 6 months in the placebo arm to 14.3 months in the treatment arm. CLARINET – Lanreotide Vs plecebo - Improvement in PFS.

48. Interferon- Alpha: category 3 - Because of its potential side effects interferon is usually not initiated until failure of somatostatin analog treatment. Mammalian Target of Rapamycin Inhibitors( Everolimus ) - approved by the US FDA for the treatment of metastatic pancreatic NETs based on improvement in PFS from 4.6 months to 11 months in a randomized study of metastatic pancreatic NETs (RADIANT-3) .

49. Angiogenesis Inhibitors - NETs are highly vascular tumors that frequently overexpress the VEGF receptor. Bevacizumab (a monoclonal antibody to circulating VEGF)- investigated in phase II clinical trials, showing disease stability in 95% of pts when combined with octrotide . Sunitinib , (an oral TKI, inhibits VEGF receptors 1, 2, and 3 as well as PDGF, cKIT )- - Demonstrated improved PFS compared to placebo in a randomized phase 3 study of advanced pancreatic NETs, which led to its approval by the US FDA for this indication in 2010

50. Systemic CT Poorly differentiated NETs, regardless of primary site, are typically treated like small-cell lung cancer with a platinum/ etoposide based regimen. no best systemic CT is yet recognised and the role of CT continues to be debated.

51. GIST

52. GIST Gastrointestinal stromal tumors (GIST) are mesenchymal neoplasms of the gastrointestinal tract-interstitial cell of Cajal GISTs are rare cancers, which were defined as a distinct disease in the 1990s, having been classified within smooth muscle neoplasms for decades from their first description in the 1960s. Coincidentally, in 2000, they became targetable by new tyrosine-kinase inhibitors (TKI).

53. GISTs can arise anywhere along the GI tract, Stomach (60%) and Small intestine (30%) are the most common primary sites. Duodenum (4% to 5%) and Rectum (4%) are the less common primary sites, and Esophagus (<1%) and colon & appendix (1% to 2%) rare site Some GISTs have been labeled as extragastrointestinal , apparently arising from the mesentery, omentum, and retroperitoneum; however, it remains unknown whether these are lesions detached from their gastrointestinal origin and/or are metastases from an unknown primary tumor.

54. Clinical features: Variety of symptoms, which may include early satiety, abdominal discomfort due to pain or swelling, intraperitoneal hemorrhage , GI bleeding, or fatigue related to anemia . Some patients may present with an acute abdomen (as a result of tumor rupture, GI obstruction, or appendicitis-like pain),which requires immediate medical attention. Liver metastases and/or dissemination within the abdominal cavity are the most common clinical manifestations of malignancy

55. outward growth of many GISTs within the gastrointestinal wall is one of the reasons why several are diagnosed relatively late, One-fourth of GISTs are discovered incidentally during diagnostic assessments (whether an endoscopic procedure, ultrasound, or computed tomography [CT] scan) done for other reasons.

56. PATHOLOGY Morphologically, GISTs can be made up of spindle cells (in more than two-thirds of cases), epithelioid cells, or both. there are no pathologic clues to make a distinction between malignant GISTs and benign. All GISTs are currently considered malignant neoplasms, although with a highly variable risk of distant relapse, which is negligible in a significant proportion of them.

57. Immunohistochemical Pattern Most GISTs (95%) express KIT (CD117). Approximately 80% of GISTs have a mutation in the gene encoding the KIT receptor tyrosine kinase; Another 5% to 10% of GISTs have a mutation in the gene encoding the related PDGFRA receptor tyrosine kinase. Other commonly expressed markers include CD34 antigen (70%), smooth muscle actin , (25%), and desmin (less than 5%). Immunohistochemical status does not reflect the mutational status with regard to KIT and PDGFRA, per se, so that it has no concrete predictive value for sensitivity to TKIs. KIT positivity alone may not be sufficient to confirm the diagnosis and, conversely, the absence of KIT and/or PDFGRA mutations does not exclude the diagnosis of GIST

58. Approximately 10% to 15% of GISTs are WT for KIT and PDGFRA. (1) SDH-deficient GISTs; (2) neurofibromatosis (NF)-1–related GISTs; or (3) others, including those with the BRAF V600E mutation. Immunohistochemically , these GIST are negative to SDHB staining.

59. DOG1 is calcium dependent, receptor-activated chloride channel protein. it is expressed in GISTs independent of mutation type. DOG1 expression was not different between the KIT/PDGFRA mutant or wild-type GIST

60. PRINCIPLES OF BIOPSY FOR GIST GISTs are soft and fragile tumors. EUS-FNA biopsy of primary site is preferred over percutaneous biopsy (due to the risk for hemorrhage and intra-abdominal tumor dissemination). Biopsy is necessary to confirm the diagnosis of primary GIST prior to the initiation of preoperative therapy. Percutaneous image-guided biopsy may be appropriate for confirmation of metastatic disease Testing for mutations in KIT and PDGFRA is strongly recommended. Testing for germline mutations in the SDH genes should be considered for patients with wild-type GIST (lacking KIT or PDGFRA mutations).

61. PRINCIPLES OF SURGERY FOR GIST Primary ( Resectable ) GIST Surgery is the primary treatment for all patients with GISTs (2 cm or greater) that are resectable without significant risk of morbidity. Aim is to resect the tumor with histologically negative margins. wedge or segmental resection of the involved gastric or intestinal tract, with margins that can be less wide than for an adenocarcinoma . complex multi-visceral resection should be avoided. If the surgeon feels that a multi-visceral resection may be required, then multidisciplinary consultation is indicated regarding a course of preoperative imatinib .

62. Lymphadenectomy is usually not required given the low incidence of nodal metastases. As GIST tends to be very friable, every effort should be made not to violate the pseudocapsule of the tumor. A macroscopically complete resection with negative or positive microscopic margins (R0 or R1 resection, respectively) is associated with a better prognosis than a macroscopically incomplete excision (R2 excision) (exception are GIST of the rectum-where microscopically positive margins are clearly associated with a higher risk of local failure.)

63. Laparoscopic approach may be considered in favorable anatomic locations (greater curvature or anterior wall of the stomach, jejunum, and ileum) by surgeons with appropriate laparoscopic experience. • Resection specimens should be removed from the abdomen in a plastic bag to prevent spillage or seeding of port sites.

64. Targeted Therapy Imatinib , a selective inhibitor of the KIT protein tyrosine kinase, has produced durable clinical benefit and objective responses in most patients with GIST. In February 2002, the FDA approved of imatinib for the treatment of patients with KIT-positive

65. Sunitinib TKI inhibiting KIT and PDGFRA but also displaying antiangiogenic activity by the inhibition of vascular endothelial growth factor receptor (VEGFR)1, 2, and 3 Standard second-line therapy.(Cat-1) January 2006, sunitinib received FDA approval. It was shown to be effective at increasing progression-free survival by 5 months in a randomized trial versus placebo in patients failing (or intolerant) to imatinib

66. Regorafenib , another TKI with activity on KIT and PDGFRA as well as VEGFR1, 2, and 3, and thus with antiangiogenic properties, standard third-line therapy for advanced GIST patients. (Cat-1) In fact, it was shown to be effective as a third-line therapy in patients failing both imatinib and sunitinib , by providing a median advantage of 4 months of progression-free survival over placebo in a randomized clinical trial

67. Two separate phase III studies EORTC 62005 study and S0033/CALGB 150105 study have assessed the efficacy of imatinib at two initial dose levels (400 mg daily vs. 800 mg daily) in patients with metastatic or unresectable GIST. Both studies showed equivalent response rates and OS for both dose levels. Higher dose of imatinib was associated with more side effects than the lower dose in both studies.

68. Primary resistance is defined as the evidence of clinical progression developing during the first 6 months of imatinib therapy and it is most commonly seen in patients with; - KIT exon 9 mutations, - PDGFRA exon 18 D842V mutations, or - tumors that lack identifiable activating mutation in KIT or PDGFRA (SDH-deficient / WT GIST. Secondary resistance is seen in patients who have been on imatinib for more than 6 months with an initial response or disease stabilization followed by progression, Mechanism- occurrence of new mutations to the same primarily mutated oncogene , or, less frequently, - oncogene amplifications or alterations of alternative pathways. Dose escalation to 800 mg/day or switching to sunitinib is a reasonable option for patients progressing on imatinib 400 mg/day

69. Termination of imatinib in patients with GIST that is refractory to imatinib has been shown to result in a flare phenomenon , which in turn indicates that even in patients with progressive disease on imatinib therapy, there are some tumor cells for which imatinib may still be effective.

70. Preoperative imatinib The RTOG 0132/ACRIN 6665 First prospective study that evaluated the efficacy of preoperative imatinib (600 mg/day) in patients with potentially resectable primary disease (30 patients) or potentially resectable recurrent or metastatic disease (22 patients). The estimated 2-year OS rate was 93% and 91% for patients with primary GIST and those with recurrent or metastatic GIST, respectively. The estimated 2-year PFS rate was 83% and 77%, respectively.

71. I ndications: - treatment for patients with GIST that is resectable with negative margins but with a significant risk of morbidity. - big abdominal masses that may be felt by the surgeon as implying a significant risk of tumor rupture during surgery Close monitoring is essential, because some patients may rapidly become unresectable. The guidelines recommend an initial dose of 400 mg daily. Patients with documented KIT exon 9 mutations may benefit from dose escalation up to 800 mg daily (given as 400 mg twice daily), as tolerated.

72. Baseline CT with or without MRI is recommended prior to the start of preoperative imatinib. imatinib should be continued until maximal response (defined as no further improvement between 2 successive CT scans, which can take as long as 6–12 months). Diagnostic CT is indicated every 8 to12 weeks. If there is no progression, continuation of the same dose of imatinib is recommended and resection should be considered, if possible. Surgery is recommended -If bleeding and/or symptoms are present. -If there is progression dosing can be stopped right before surgery and resumed as soon as the patient is able to tolerate oral medications following surgery regardless of surgical margins- life long.

73. Response Assessment The radiologic response, as assessed through CT scans and MRI, is marked by - tumor shrinkage and/or - changes in tumor tissue. Response Evaluation Criteria in Solid Tumors (RECIST) criteria for tumor response assessment are based on the measurement on one diameter of selected target lesions. Choi criteria were worked out in GISTs to accommodate these patterns of response, by factoring tumor hypodensity on CT scans in addition to a decrease in size. The EORTC has developed metabolic response criteria for tumors evaluated with PET.

74. A positive PET scan may turn negative in a few days. Of course, this does not correspond to the disappearance of the tumor lesion, but rather be the consequence of the metabolic switch off that the tumor undergoes when an effective TKI targets its cells. The reverse is true as well, so that any stop of therapy rapidly entails a switch on of functional imaging.

75. Post-operative imatinib Surgery does not routinely cure GIST. Complete resection is possible in approximately 85% of patients with primary tumors. At least 50% of these patients will develop recurrence or metastasis following complete resection and the 5-year survival rate is about 50%. Median time is about 2 years.

76. ACOSOG Z9001 randomized study phase III, double-blind, Patients with primary localized GISTs (3 cm or greater in size) postoperative imatinib 400 mg (359 patients) or placebo (354 patients) for one year after complete resection. Results: The RFS rate at one year was significantly higher in the imatinib arm compared to placebo (98% and 83%, respectively, P < .001). OS was not different in both arms (99.2% vs. 99.7%, respectively; P = .47).

77. SSGXVIII/AIO: randomized phase III study suggest that postoperative imatinib administered for 36 months improves RFS and OS compared to 12 months for patients with a high estimated risk of recurrence after surgery.(mitotic index of >5 mitoses/50 HPF, size >5 cm, non-gastric location, and tumor rupture).

78. In patients who have received preoperative imatinib, regardless of surgical margins until progression. Postoperative imatinib should be initiated following resection, if the patient had not received prior imatinib therapy.

79. Unresectable or Metastatic GIST Imatinib (CAT-1)is the primary therapy for advanced, unresectable or metastatic GIST. Surgery may be indicated for: • Limited disease progression refractory to imatinib. • Locally advanced or previously unresectable tumors after a favorable response to preoperative imatinib.(if complete resection can be obtained in primary metastatic disease)

80. Several retrospective studies have demonstrated survival benefit of cytoreductive surgery following preoperative imatinib in patients with advanced or metastatic GIST responding to preoperative imatinib. Imatinib should be continued if resection is not feasible for metastatic GIST until progression. The dose of imatinib should not be increased if patients remain stable without objective progression of the disease.

81. Recurrence following complete resection should be managed as described for unresectable or metastatic disease, because recurrent disease represents locoregional metastatic or infiltrative spread of the malignancy and carries essentially the same prognosis as distant metastases overall.

82. Current risk classification systems are based on the combination of mitotic count, tumor size, and site of origin. the combination of these three factors allows one to forecast a risk of relapse by using tools such as -The Armed Forces Institute of Pathology (AFIP) risk classification, -The Memorial Sloan Kettering Cancer Center (MSKCC) nomogram , or -The contour maps.

83. Prognostic Factors Tumor size and the mitotic rate are the most widely used pathologic features for the risk stratification of GIST. The metastatic rate was 86% for tumors > 10 cm with a mitotic index of >5 mitoses/50 HPFs, whereas tumors of the same size with a mitotic index of <5 mitoses/50 HPFs have a relatively low metastatic rate of 11 %. With small intestinal GIST, tumors >10 cm with a mitotic index of ≤5 mitoses/50 HPF had a metastatic rate of 50%, which is a contrast to that reported for gastric GIST In addition to the tumor size and mitotic rate , tumor site has also been included in the guidelines developed by Miettinen and colleagues for the risk stratification of primary GIST.

84. According to these guidelines, Gastric GISTs have an overall indolent behavior and those that are ≤2 cm (irrespective of the mitotic index) are essentially benign, Small intestinal GISTs tend to be more aggressive than gastric GISTs. Rectal GISTs are also very aggressive and tumors <2 cm with a mitotic index of >5 mitoses/50 HPFs have a higher risk of recurrence and malignant potential.

85. KIT & PDGFR mutations can be found in high-grade tumors as well as in small incidental GIST and tumors that have a benign course. Therefore, KIT mutational status is not used in the routine prognostic assessment of a primary GIST.

86. Thank you