A) PUBLIC HEALTH B) PRESENTATION & DIAGNOSIS

Transcription

1 GIST (Gastrointestinal stromal tumor) Updated MARCH 2017 by Dr. Doreen Ezeife, PGY-5 Resident, University of Calgary Reviewed by Dr. Jan-Willem Henning (Staff Medical Oncologist, University of Calgary) DISCLAIMER: The following are study notes compiled by the above PGY-5 medical oncology residents and reviewed by a staff medical oncologist. They reflect what we feel is relevant knowledge for graduating medical oncology residents preparing for their final examination. The information has not been surveyed or ratified by the Royal College. A) PUBLIC HEALTH EPIDEMIOLOGY - Incidence: Rare tumor that accounts for less than 1% of all GI cancer, cases per million populations per year. - More common in: Men, black and middle age and elderly (mean age at diagnosis is 63). - Location: GIST can occur in any part of GI tract, stomach 65%, small intestine 25%, others in rest of GI tract or in abdomen (ASCO SEP). - Survival: 5 year overall survival is more than 75% in localized, 65% in regional and 40% in metastatic. RISK FACTORS - Most of the GIST cases are sporadic. - Genetic: - 1- Familial GIST: mutations in KIT gene, multiple gastric and small intestine GIST, skin hyperpigmentation, dysphagia and paragangliomas Neurofibromatosis type 1 (NF1): multiple, mainly small intestine and wild type KIT. PREVENTION & SCREENING - Prevention: Not known. - Screening: No available data. B) PRESENTATION & DIAGNOSIS SYMPTOMS & SIGNS - Common Symptoms: Depends on the location of the tumor. Abdominal pain, GI bleeding, early satiety and other non-specific symptoms (N/V). - Common Signs: Abdominal mass, bowel obstruction and incidental findings. INVESTIGATIONS - Laboratory: CBC to check for anemia, LFT and kidney function. - Diagnostic Imaging: CT or MRI, Upper or lower endoscopy and EUS. PET will show metabolic activates in GIST but not routinely used. - Diagnostic Procedures: FNA can be sufficient to make the diagnosis. Preferred core-biopsy tissue. PATHOLOGY & MOLECULAR BIOLOGY - Common Histology: GIST typically present as subepithelial tumors, spindle cell type 70%, epithelioid type 20% and mixed type 10%. - Common Metastatic Sites: liver and peritoneum. - Molecular Biology: 95% KIT positive (CD117), 70% CD34 positive. DOG-1 (Discovered On GIST -1) positive in almost all GISTs and used in negative KIT to confirm the diagnosis. Most GISTs have activating mutations in KIT or platelet-derived growth factor alpha (PDGRA) gene. - All guidelines recommend confirming the morphological diagnosis with IHC, either CD117 and/or DOG-1.

2 STAGING - TNM: Not commonly used by medical oncologist. Instead most oncologists used the modified NIH risk stratifications. Very Low Risk Low Risk Intermediate Risk High Risk Modified NIH consensus classification (used in the SSGXVIII/AIO study) (15) Any location: <2 cm and 5 Any location: cm and 5 mitotic Gastric: cm and 5 ; 5 cm and 6 10 Any location: tumor rupture; >5 cm and >5 ; >10 cm; >10 Non-gastric: 5 cm and >5 ; cm and 5 Tumor rupture Other risk stratifications commonly used Very Low Risk Low Risk Intermediate Risk High Risk NIH consensus criteria (15) AFIP classification system (criteria used in NCCN and ESMO guidelines) (16, 17) <2 cm and <5 Gastric: 2 cm and any ; 5 cm and 5 Non-gastric: 2 cm and cm and <5 mitotic Gastric: >5 cm and 10 cm, and 5 Nongastric: >2 cm and 5 cm, and cm and <5 ; <5 cm and 6 10 Gastric:>10 cm and 5 mitotic ; >2 cm and 5 cm, and >5 Jejunal or ileal: >5 cm and 10 cm, and 5 >5 cm and >5 ; >10 cm; >10 Gastric: >5 cm and >5 mitotic Duodenal or rectal: >5 cm Non-gastric:>10 cm; >5 mitotic Modified NIH consensus classification (used in the SSGXVIII/AIO study) (18) Any location: <2 cm and 5 Any location: cm and 5 Gastric: cm and 5 mitotic ; 5 cm and 6 10 mitotic Any location: tumor rupture; >5 cm and >5 ; >10 cm; >10 Non-gastric: 5 cm and >5 ; cm and 5 Tumor rupture Prognostic factors: The most important independent factor for GIST recurrence is high mitotic rate. Other factors include large tumor size, site and tumor rupture. Gastric GIST has the lowest risk for recurrence. Extra- GI GIST has the highest recurrence rate (Omentum, mesentery and retroperitoneum).

3 Mutation of PDGFRA has a favorable outcome. Alteration of KIT exon 9, deletion in KIT exon 11 is associated with more tumor recurrence C) TREATMENT LOCALIZED: NEOADJUVANT THERAPY There are no phase III randomized trials being done to assess preop Imatinib, however, a few phase II nonrandomized trials have been done. Neoadjuvant Imatinib can be considered for patients with unresectable GIST or where surgery will cause significant morbidity, and downsizing the tumor bulk will help to preserve organ function. The usual duration is 9-12 months of preoperative Imatinib (until plateau in response has been reached). Close monitoring with imaging studies is required to ensure therapy response every 3 months. ADJUVANT THERAPY - Surgical resection followed by adjuvant Imatinib if indicated (in high risk of recurrence, maybe in intermediate risk but not in low risk) Survival (OS) benefit ONLY in HIGH Risk group based on Modified NIH criteria. Intermediate group will derive DFS benefit but not OS. - Prognosis: Depends on risk of recurrence. (Use Memorial Sloan Kettering Nomogram to predict recurrence risk and prognosis) - Recommendations: Adjuvant Imatinib in resected GIST for 3 years is superior to 1 year. After 3 years is not known. - Follow up: From the randomized clinical trials for adjuvant therapy: physical exam and blood work every 1-3 months, while on treatment CT 3-6 months, then every 6 months to complete 5 years then annually. - Important Phase III Clinical Trials: ACOSOG Z9001 Dematteo RP et al, Lancet 2009;373(9669):1097 Regimen Imatinib 400 mg po OD vs. placebo for one year Mechanism of TKI that inhibits BCR-ABL, PDGFR, stem cell factor and c-kit. Primary Endpoint RFS Inclusion/Exclusion (At least 3 cm, IHC + for KIT) Size (N) 713 patients Results Survival: Imatinib added one year more of protection but no overall survival. RFS: One year was 98% vs 83% Toxicity (N/V, ankle and periorbital edema, fluid retention, diarrhea, myelosuppression and skin rash)

4 SSG XVIII trial Joensuu H et al, JAMA Mar;307(12): Regimen Imatinib 400 mg po OD for 3 years vs. Imatinib 400 mg po OD for for one year. Mechanism of TKI that inhibit BCR-ABL, PDGFR, stem cell factor and c-kit. Primary Endpoint RFS Inclusion/Exclusion GIST + KIT and high risk (Tumor size >10 cm, mitotic count >10/50 hpf, tumor size >5 cm with mitotic rate >5/hpf, or tumor rupture) Size (N) 400 patients Results Survival: 5 years 92% vs. 82% RFS: 5 years 66% vs. 48% Toxicity Periorbital edema (74 versus 59 %), diarrhea (54 versus 44 %), and muscle cramps (49 versus 31 %) Conclusion Compared with 12 months of adjuvant imatinib, 36 months of imatinib improved RFS and overall survival of GIST patients with a high risk of GIST recurrence

5 METASTATIC - Bottom Line General Approach: If the primary and metastatic site can be resected, combination of Imatinib and surgical resection is recommended. Palliative surgery and/ or XRT can be considered in symptomatic patients (e.g GI bleeding) Palliative Imatinib 400 mg PO OD as 1 st line, dose escalation when progressed to 800mg OD. Especially those with exon 9 mutation 2 nd line Sunitinib, 3 rd line Regorafenib. - Prognosis: (median survival with Imatinib is 57 months and without treatment is 18) - Important Phase III Clinical Trials: 1 st line: US Intergroup Blanke CD et al, Clin Oncol. 2008;26(4):626. Regimen Imatinib 400mg OD vs. 400mg BID Mechanism of TKI that inhibit BCR-ABL, PDGFR, stem cell factor and c-kit. Primary Endpoint PFS Inclusion/Exclusion Metastatic or surgically unresectable GIST Size (N) 746 patients Results Survival: median survival, 55 vs. 51 months PFS: 18 vs. 20 months Toxicity More grade 3,4 and 5 side effects in higher dose arm Conclusion This trial confirms the effectiveness of imatinib as primary systemic therapy for patients with incurable GIST but did not show any advantage to higher dose treatment. It appears reasonable to initiate therapy with 400 mg daily and to consider dose escalation on progression of disease 1 st line: EORTC Verweij J et al, Lancet. 2004;364(9440):1127 Regimen Imatinib 400mg OD vs. 400mg BID Mechanism of TKI that inhibit BCR-ABL, PDGFR, stem cell factor and c-kit. Primary Endpoint PFS Inclusion/Exclusion Metastatic GIST Size (N) 946 patients Results PFS 2 year 50% vs. 56% Conclusion If response induction is the only aim of treatment, a daily dose of 400 mg of imatinib is sufficient; however, a dose of 400 mg twice a day achieves significantly longer progression-free survival.

6 Imatinib Resistance: Imatinib pharmacokinetics Can be different from patient to other, low trough level of imatinib 1 month after starting is associated with shorter time to progression < 1100 ug/l, this can be seen with patients who underwent subtotal or total gastrectomy, measurement of trough concentration after 3 months of starting and increasing the dose might be considered. Tumor Genotype: v KIT with no mutation >> less sensitive to Imatinib but more sensitive to Sunitinib and Regorafenib. v KIT exon 9 mutation >> less sensitive to Imatinib but more sensitive to Sunitinib. Higher dose of Imatinib 800mg OD in metastatic GIST more effective than 400mg. v KIT exon 11 mutation >> more sensitive to Imatinib, less sensitive to Sunitinib. v PDGFRA with no mutations >> less sensitive to Imatinib but more sensitive to Sunitinib and Regorafenib. 2 nd line Efficacy and safety of sunitinib in patients with advanced GIST after failure of imatinib Demetri GD et al Lancet. 2006;368(9544):1329 Regimen Suitinib 50 mg po OD 4 weeks and 2 weeks off vs. placebo Mechanism of Multi TKI, inhibit PDGFR alpha and beta, VEGF R1,2,3 and c-kit, RET Primary Endpoint Time to tumor progression Inclusion/Exclusion Advanced gastrointestinal stromal tumour who were resistant to or intolerant of previous treatment with imatinib Size (N) 312 patients 2:1 ratio Results TTP 27 vs, 6 weeks mos could not calculate a mos. HR 0.49 (p=0.007) Toxicity Fatigue, nausea, vomiting, anemia, neutropenia, diarrhea, abdominal pain, mucositis, anorexia, hypothyroidism, and discoloration of skin and hair, HTN CHF, hand-foot skin reaction and proteinuria Conclusion Significant TTP and although survival was significantly better with sunitinib in the initial report, over time Overall survival converged. Cross over was allowed.

7 3 rd line: Efficacy and safety of regorafenib for GIST after failure of imatinib and sunitinib Demetri GD et al, Lancet. 2013;381(9863):295. Regimen Regorafenib 160 mg daily or placebo 3/4 weeks Mechanism of Multi TKI, inhibit PDGFR alpha and beta, VEGF R1,2,3 and c-kit, RET, RAF-1, BRAF Primary Endpoint PFS Inclusion/Exclusion Advanced gastrointestinal stromal tumour that were resistant to previous treatment with imatinib and sunitinib. Size (N) 199 patients 2:1 ratio Results PFS 4.8 vs. 0.9 months No OS because of crossover design. Toxicity Fatigue, HTN, Hand-foot skin reaction and diarrhea Conclusion Regorafenib can provide a significant improvement in progressionfree survival compared with placebo in patients with metastatic GIST after progression on standard treatments. D) REFERENCES The epidemiology of malignant gastrointestinal stromal tumors: an analysis of 1,458 cases from 1992 to Tran T, Davila JA, El-Serag HB, Am J Gastroenterol. 2005;100(1):162. Fletcher CD, Berman JJ, Corless C, Gorstein F, Lasota J, Longley BJ, Miettinen M, O'Leary TJ, Remotti H, Rubin BP, Shmookler B, Sobin LH, Weiss SW, Hum Pathol. 2002;33(5):459. US population data from the US Census bureau, (Accessed on March 08, 2011). Epidemiology of gastrointestinal stromal tumors in the era of histology codes: results of a population-based study. Ma GL, Murphy JD, Martinez ME, Sicklick JK, Cancer Epidemiol Biomarkers Prev. 2015;24(1):298 Maeyama H, Hidaka E, Ota H, et al. Familial gastrointestinal stromal tumor with hyperpigmentation: association with a germline mutation of the c-kit gene. Gastroenterology 2001; 120:210. Watson RR, Binmoeller KF, Hamerski CM, et al. Yield and performance characteristics of endoscopic ultrasound-guided fine needle aspiration for diagnosing upper GI tract stromal tumors. Dig Dis Sci 2011; 56:1757. Novelli M, Rossi S, Rodriguez-Justo M, et al. DOG1 and CD117 are the antibodies of choice in the diagnosis of gastrointestinal stromal tumours. Histopathology 2010; 57:259. Blanke CD, Demetri GD, von Mehren M, et al. Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol 2008; 26:620. NCCN. Soft Tissue Sarcoma Version I Accessed August 25, ESMO/ European Sarcoma Network Working Group. Gastrointestinal stromal tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2014; 25(sup 3): iii21-iii26 Agaimy A. Gastrointestinal stromal tumors (GIST) from risk stratification systems to the new TNM proposal: more questions than answers? A review emphasizing the need for a standardized GIST reporting. Int J Clin Exp Pathol 2010; 3(5): Gastrointestinal stromal tumor. Joensuu et al. Lancet 2013; 382: Eisenberg BL, Harris J, Blanke CD, et al. Phase II trial of neoadjuvant/adjuvant imatinib mesylate (IM) for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumor (GIST): early results of RTOG 0132/ACRIN J Surg Oncol 2009; 99(1): 42-7

8 Andtbacka RH, Ng CS, Scaife CL, et al. Surgical resection of gastrointestinal stromal tumors after treatment with imatinib. Ann Surg Oncol 2007; 14(1): Raut CP, Posner M, Desai J, et al. Surgical management of advanced gastrointestinal stromal tumors after treatment with targeted systemic therapy using kinase inhibitors. J Clin Oncol 24(15):