Neuroendocrine Tumor Chemotherapy

1. Neuroendocrine Tumor Chemotherapy Dr. Ali Okhovatian. M.D. Active Member of American Society of Clinical Oncology Nov 14, 2018

2. Histologic Classification of NET • NET are generally subclassified by site of origin , stage, and histologic characteristics. • Tumor differentiation and grade often correlate with mitotic count and Ki-67 proliferation index. • Increased mitotic rate and high Ki-67 index are associated with a more aggressive clinical course and worse prognosis.

3. Histologic Classification of NET,Cont • In some cases, however, tumors may not fall clearly into one category. For example, a morphologically well-differentiated NET with a low mitotic index may have a Ki-67 index that falls into the high-grade category. • A key recommendation is that tumor differentiation, mitotic rate, and Ki-67 index should all be included in the pathology report.

4. Histologic Classification of NET , Con • The classification of lung and thymus carcinoids varies from that of gastroenteropancreatic NET in some classification systems, and in particular does not include Ki-67 and includes the assessment of necrosis. • In NET unlike other malignancies, primary tumor size and depth of invasion had little bearing on survival in early-stage disease.

5. Histologic Classification of NET, con • Presence of lymph node and distant metastases have the strongest effect on survival. • In addition to information on histologic classification and stage, the margin status , and the presence of vascular or perineural invasion may also have prognostic significance.

6. Histologic Classification of NET , con • Whether or not tumors are associated with symptoms of hormone hypersecretion (“functioning” or “ non-functioning”) is, in general, a part of the clinical rather than histologic diagnosis. Thus , functional status is usually not included in the pathology report. However, If a specific clinical situation suggests that correlation with histologic evidence of peptide hormone may be helpful, then biochemical or IHC may be performed.

7. Management of Locoregional NET • Resection is the primary treatment approach for most localized carcinoid tumors. • Although symptoms of hormone hypersecretion are more common in metastatic disease, with locoregional disease with this symptoms, we can use octreotide or lanreotide.

8. Thymic NET • Localized or locoregional disease are generally treated with surgical resection without adjuvant therapy if negative margin. • There is limited data on the utility of radiation with or without chemotherapy for unresectable disease or positive margins.

9. Thymic NET, con • RT is considered category 3 for low-grade (atypical) tumors. • In intermediate grade tumor(atypical) , RT with or without cisplatin or carboplatin and etoposide is more generally recommended, because they have greater efficacy in tumors with higher mitotic and proliferative index.

10. Bronchopulmonary NET • Surgery including lobectomy or other anatomic resection, and mediastinal node dissection or sampling is recommnded for stage I,II, and IIIA. If surgery is feasible and disease in stage I,II, or low-grade IIIA, patients may be monitored with surveillance. If stage IIIA is intermediate grade, adjuvant therapy using chemotherapy with or without RT may be considered.

11. Bronchopulmonary NET, con • There is limited data on the efficacy of chemoradiation for unresectable stage IIIA or IIIB. • If surgical resection is not medically feasible , or if there are positive margins following resection for patients with low-grade, or if patients have low-grade stage IIIB, then RT with or without chemotherapy is considered by some panel( category 3).

12. BronchopulmonaryNET,con • If stage IIIA or IIIB are intermediate grade, RT with or without chemotherapy is generally recommended.

13. Appendiceal NET • A small proportion of these tumors may also contain evidence of adenocarcinoma (ie, “adenocarcinoid” or “ goblet cell carcinoid”). These should be managed according to colon cancer.

14. Evaluation of Locoregional/distant Metastatic GI, Bronchopulmonary, and Thymic NET • Poorly differentiated bronchopulmonary or thymic tumors may have less avidity for 68 Ga- dotatate PET/CT, therefore FDG-PET/CT may be considered for NETs that are poorly differentiated or have atypical histology.

15. Management of LocoregionalUnresectable/Metastatic GI NET • Patients with metastatic NET and carcinoid syndrome should be treated with octreotide or lanreotide. The long-acting release (LAR) formulation of octreotide, 20-30 mg IM every 4 wk, is commonly used for chronic symptom management. But therapeutic levels are not achieved for 7-14 days, so short-acting octreotide ( 150- 250 mcg SC 3 times daily) can be added for rapid relief of symptoms.

16. Management of LocoregionalUnresectable/Metastatic GI NET,con • Lanreotide has similar mechanism of action as octreotide. Several studies have shown it to be effective at controlling symptoms in patients with carcinoid tumors, gastrinomas, or VIPomas.

17. Management of LocoregionalUnresectable/Metastatic GI NET,con • If carcinoid tumor is poorly controlled, telotristat, small molculetrytophanhydoxylase (TPH) inhibitor, which decreases urinary 5-HIAA levels and the frequency of bowel movement, should be considered. It was approved by the FDA in February 2017 and recommended for persistent diarrhea.

18. Resection of Metastatic disease • In some cases, limited hepatic metastases or other sites of disease can undergo complete resection of primary tumor and metastases with curative intent. • Noncurativedebulking surgery can also be considered in select cases, especially if the patient is symptomatic either from tumor bulk or hormone production.

19. Resection of Metastatic disease, con • 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.

20. Hepatic-directed Therapies for Metastatic NET of GI tract • For patients with unresectable, hepatic-predominant, progressive disease, may be considered, mainly for palliative goals of extending life and relieving hormonal symptoms ( RFA or cryoablation, hepatic arterial embolization or chemoembolization).

21. Therapy for Advanced GI NET • Everolimus ( an inhibitor of mTOR) can be considered for progressive metastatic GI carcinoids. It can be given with octreotide LAR. Adverse events include: stomatitis, fatigue, rash, and diarrhea.

22. Therapy for Advanced Bronchopulmonary or Thymic NET • Patients with advanced intermediate-grade should generally be initiated on systemic therapy. Options include; octreotide or lanreotide, everolimus, temozolamide. Carboplatin or cisplatin and etoposide is generally considered for tumors on the higher end of atypical category with respect to Ki-67 and grade. These drugs may be given with or without octreotide.

23. Therapy for LocoregionalresectablePancreatic NET • For Insulinoma, first stabilizing glucose levels with diet and/or diazoxide. Also we can use everolimus in this scenario. • For Glucagonoma, hypercoagulable state reported in 10% to 33%, so perioperative anticoagulation can be considered, because of increased risk of pulmonary emboli.

24. Therapy for Locoregional/ Metastatic Pancreatic NET • Unfortunately, most patients who present with pancreatic NET have unresectable disease. For patients who are asymptomatic and have low tumor burden and stable disease, observation can be considered, with marker assessment and abdominopelvic CT or MRI every 3 to 12 months until clinically significant progression occurs.

25. Therapy for Locoregional/ Metastatic Pancreatic NET,con • For symptomatic patients with unresectable disease, those who initially present with clinically significant tumor burden, or those with clinically significant disease progression, options include: octreotide or lanreotide; if disease continue to progress: everolimus or sunitinib, or treatment with cytotoxic chemotherapy.

26. Therapy for Locoregional/ Metastatic Pancreatic NET,con • The molecularly targeted agents everolimus and sunitinib have been confirmed to have antitumor activity and to improve PFS in patients with advanced pancreatic NET. • Streptozocin is FDA-approved for use in patients with advanced pancreatic NET. • Temozolamide has activity at least comparable to streptozocin in Pancreatic NET.

27. Therapy for Nonmetastatic Adrenal Carcinoma • Adjuvant therapy may be considered if the patient is at high risk for local recurrence based on positive margins, ruptured capsule, large size, or high grade. Adjuvant RT to the tumor bed can be considered in these cases, particularly if concern exists regarding tumor spillage or close margins after surgery.

28. Therapy for Metastatic Adrenal Carcinoma • Resection may be considered if greater than 90% of the tumor and metastases can be removed. Otherwise, systemic therapy should be initiated. • Choices of systemic therapy are mitotanemonotherapy or various combinations of cisplatin, carboplatin, etoposide, streptozocin, and mitotane.

29. Therapy for Metastatic Adrenal Carcinoma,con • Pembrolizumab ( an Ig G4 isotype antibody) should be considered in mismatch repair- deficient (dMMR) or microsatellite instability – high (MSI-H) unresectable/metastatic adrenocortical tumors that have progressed following prior treatment and have no satisfactory alternative treatment options.

30. Therapy for Pheochromocytoma/Paraganglioma • For locally unresectable tumors, RT can be considered, with cytoreductive resection, when possible. Alternatively, if tumors are positive on MIBG scan with dosimetry, treatment with iodine-131- MIBG therapy is recommended.

31. Therapy for Pheochromocytoma/Paraganglioma,con • When distant metastases are present, cytoreductive resection is also recommended when possible, and medical therapy should be continued for secreting tumors. Other options for unresectable/ metastatic include: 1) systemic chemotherapy (CVD or temozolamide), 2) iodine-131-MIBG therapy, or 3) palliative RT for bone metastases.

32. High grade or Poorly differentiated NET/ Large or Small cell carcinoma • Most extrapulmonary poorly differentiated NET are aggressive and require treatment similar to small cell lung cancer. • For resectable tumors, surgical resection and chemotherapy with or without RT are advised. Alternatively, definitive chemoradiation can be considered.

33. High grade or Poorly differentiated NET/ Large or Small cell carcinoma,con • For unresectablelocoregional disease, RT in combination with chemotherapy is recommended. • If metastatic tumors are present, chemotherapy alone is recommended (cisplatin or carboplatin with etoposide).

34. Thank you for your attention