An odyssey into the land of rare tumours: adenocarcinoma of small bowel and endocrine tumours

1. An odyssey into the land of rare tumours: adenocarcinoma of small bowel and endocrine tumours Monika Krzyzanowska, MD MPH MOTP Half-day March 27th, 2009

2. Objectives • Review the management of the following tumours with a focus on systemic therapy and the role of medical oncologist in management: • Small bowel adenocarcinoma • Neuroendocrine tumours of the GI tract • Thyroid carcinoma

3. Small Bowel Neoplasms (SEER)

4. Small Bowel Adenocarcinoma

5. Epidemiology (1) • Extremely rare tumour (<< 1% of all malignancies) • Most common presenting symptoms: • Abdominal pain • Obstruction • Bleeding • Main risk factor - Crohn’s disease

6. Epidemiology (2) • Most frequent site is duodenum (approx 50%) followed by jejunum & ileum • About 1/3 present with metastatic disease • Most common metastatic sites - liver and peritoneum

7. Diagnosis • Difficult to diagnose because of lack of optimal non-invasive modalities to image the small bowel • Most frequently diagnosed intraoperatively, by CT or at time of gastroscopy (duodenal tumours) • Emerging modalities – video capsule endoscopy, PET scans

8. Staging (1)

9. Staging (2)

11. Prognosis • Median overall survival in retrospective series approximately 18 months; <12 months with metastatic disease • 5-yr overall survival (all stage) about 25% • Recurrences tend to be distal rather than local

12. Surgery • The only potentially curative option • 5 yr survival 20-60% • No definite standard type of surgery (segmental resections  Whipple procedure) although retrospective studies suggest patients with proximal tumours may do better after Whipple

13. Systemic Therapy (1) • Lack of prospective data on the role of chemotherapy in either the adjuvant or metastatic setting • Most information comes from retrospective reviews usually from single institutions • These suggest about 30% of patients receive adjuvant tx

14. Systemic Therapy (2) • Chemotherapy regimens have generally been extrapolated from gastric, pancreas, stomach or colon cancer protocols • Commonly used agents: • 5FU • Cisplatin • Irinotecan • Gemcitabine • Response rates have been described (incl CR) and studies suggest survival benefit but difficult to control for selection bias given lack of prospective, controlled trials

15. Systemic Therapy: PMH Experience (N = 113*) *not all patients received chemo Adapted from Fishman et al, AJCO 2006 **includes capecitabine

16. Small bowel adenoca: Bottom line • Role of adjuvant chemotherapy uncertain • Chemotherapy may be worthwhile in selected patients with advanced disease • Optimal regimen not clear but gemcitabine or irinotecan (single agent or in combination with 5FU) probably best first-line choices

17. Neuroendocrine Tumours (NET) of the GI Tract

18. FOREGUT Respiratory tract Thymus Stomach, pancreas & proximal duodenum MIDGUT Jejunum, ileum, appendix Ascending colon HINDGUT Transverse and descending colon rectum Anatomic Classification

19. GI tract NETs: Epidemiology • Majority arise in midgut • Incidence increasing • Appendix is the most common site followed by small bowel • Can be functional (ie. secrete various hormones such as gastrin, hCG, serotonin) or non-functional • Can be benign or malignant • Most common metastatic sites are liver & bone

20. Pathology • Classification is evolving • Should be reviewed by a pathologist with expertise in neuroendocrine tumours • Special stains include: • Neuron specific enolase • Synaptophysin • Chromogranin • Mitotic count +/- Ki67 antigen to assess rate of proliferation • Grade of differentiation – may affect management

21. Grading proliferation of well-differentiated NETs Rindi et al, Virchows Arch 2006; 449:399

22. Carcinoid Syndrome • Syndrome associated with excess of serotonin, histamine or tachykinins • Symptoms/signs: • Episodic flushing • Diarrhea • Cardiac disease (right sided valvular disease) • Tends to occur when tumour in close contact with systemic circulation: • Liver metastases • Bronchial or ovarian carcinoids • Treatment consists of somatostatin analogues which inhibit hormone release

23. Baseline Investigations (1) • Depends in part on location • Labs: • Chromogranin A –not easily available • Urine 5-HIAA (breakdown product of serotonin) • Imaging • CT/MRI (contrast essential) • Octreoscan (somatostatin receptor scintigraphy) • Endoscopic U/S (pancreatic tumours) • +/- Bone scan • Standard PET (18F-fluorodeoxyglucose) not helpful; better with other tracers (5-hydroxy-L-tryptophan), but not easily available

24. Baseline Investigations (2) • Other: • 2D Echo in selected patients (symptoms suggestive of carcinoid syndrome, murmur or elevated 5HIAA levels)

25. Staging • A TNM based system has been recently proposed albeit not being yet used Rindi et al, Virchows Arch 2006; 449:399 • Usually classified into: • Localized • Locoregional • Metastatic

26. Prognosis • Overall, 5 year survival approx. 67% • Highly variable (usually measured in years), correlated with: • Stage • Size (esp in appendiceal & rectal carcinoids) • Location • Differentiation

27. Management of Recurrent/Metastatic NET

28. Management Overview • Treatment depends on: • Symptoms • Presence/lack of hormone excess • Location of metastatic disease • Rate of growth • Histologic differentiation • Patient preference

29. Somatostatin Analogues • Control hypersecretion of neuropeptides in foregut & midgut carcinoids that express somatostatin receptors • Available as a short or long-acting injection • Until recently was predominantly indicated for symptom control and to prevent complications in carcinoid syndrome • Anti-tumour effects have been a matter of debate –occasional responses have been described, disease stabilization more common • Tachyphylaxis can develop over time

36. Liver Only Disease • Surgical resection/debulking if feasible • Bland embolization • Chemoembolization • Radiofrequency ablation

37. Metastatic Disease not Amenable to Local Tx • Treatment depends on symptoms and rate of clinical/radiologic progression • For asymptomatic/slow growing tumours consider octreotide (F/U q3-6 months) • For symptomatic/rapidly growing tumours may consider systemic therapy, preferably as part of clinical trial

38. Poorly Differentiated Tumours • Thought to be related to small cell carcinoma of lung • Usually treated with platinum-based regimens often VP16/cisplatin • RR up to 67% have been reported including CRs (Moertel Cancer 1991)

39. Well-differentiated Tumours (1) • Number of phase 2/3 studies over the last 30 yrs • Less responsive to chemotherapy esp non–islet cell tumours • Usually treated with streptozotocin-based therapy • Limited response to cisplatin/VP16 (<<20%) • Limited activity of newer agents (gemcitabine, taxanes)

40. Chemotherapy for well-differentiated tumours

41. Quality of Evidence • Many methodologic concerns with existing trials: • Different patient populations • Large numbers of inevaluable pts • Assignment based on previous tx or comorbid conditions in randomized studies • Use of physical exam or biochemical response to evaluate efficacy

42. Chemotherapy for well-differentiated tumours • Generally better RR in islet-cell tumours • Whether survival advantage exists for streptozotocin + doxorubicin vs streptozotocin + 5FU not clear: • survival advantage for doxorubicin combination in one study (2.2 vs 1.4 years STZ/dox vs STZ/5FU) Moertel NEJM 1992 • survival advantage for 5FU combination in another (24.3 vs 15.7 months STZ/5FU vs STZ/dox) Sun JCO 2005

43. Emerging Therapies • Promising/ongoing: • radiolabelled somatostatin & MIBG analogues +/- chemo • Ineffective: • Endostatin • Single agent thalidomide (more promising in combination with chemotherapy) • Imatinib • Bortezomib

44. NET Bottom line (1) • Consider whether curative/debulking surgery warranted • Recent evidence suggests that there is a role for long-acting octreotide in many pts – not just those with biochemical evidence of hormone excess +/- symptomatic carcinoid syndrome

45. NET Bottom line (2) • Liver-directed therapies for patients with liver predominant disease • Consider chemotherapy in patients with symptomatic disease not amenable to local tx: • Streptozotocin-based for well-differentiated tumours • Cisplatin/VP16 in poorly differentiated tumours • Clinical trials!

46. Thyroid Cancer

47. Histologic Classification ThyroidCancer Medullary Differentiated Anaplastic Hereditary Sporadic Papillary Follicular

48. Differentiated Thyroid Tumours • Account for approximately 80-90% of all thyroid malignancies • Originate from follicular epithelial cells within the thyroid • Broadly split into papillary or follicular tumours • Prognostic factors include age, size, histologic grade, lymph node involvement

49. Medullary Thyroid Cancer • Arise from the parafollicular C-cells of the neural crest • 70% sporadic • 30% hereditary • Familial medullary thyroid cancer not associated with MEN • MEN 2A (pheochromocytomas, hyperparathyroidism) • MEN 2B (pheochromocytomas, neuromas)

50. DIFFERENTIATED Surgery Thyroid hormone replacement +/- 131I +/- external beam radiation therapy MEDULLARY Surgery +/- external beam radiation therapy Treatment of Early Stage Disease