- Email: [email protected]
Management of Intractable Hypoglycemia With Yttirum-90 Radioembolization in a Patient With Malignant Insulinoma
CASE REPORT
Management of Intractable Hypoglycemia With Yttirum-90 Radioembolization in a Patient With Malignant Insulinoma Prakash Chandra, MD, Shadi Sadeghi Yarandi, MD, Natasha Khazai, MD, Sol Jacobs, MD and Guillermo E. Umpierrez, MD
Abstract: Metastatic insulinomas may present with recurrent lifethreatening hypoglycemia. Treatment of hypoglycemia in such patients is difficult and frequently fails to respond to numerous therapeutic agents, requiring continuous dextrose infusion. The authors present our experience with Yttirum-90 radioembolization in a patient with metastatic malignant insulinoma who failed to respond to distal pancreatectomy, systemic chemotherapy with capecitabine and everolimus and medical treatment with somatostatin analogues, diazoxide and corticosteroids. Treatment with repeated Y-90 radioembolization resulted in rapid resolution of hypoglycemic events, allowing discontinuation of dextrose infusion and hospital discharge. However, the effect of Y-90 administration seems to be transient and without evidence of tumor shrinkage in imaging studies. Key Indexing Terms: Insulinoma; Hypoglycemia; Malignant insulinoma; Yttirum-90; Octreotide therapy. [Am J Med Sci 2010;340(5):414–417.]
I
nsulinoma is a rare islet cell tumor of pancreas with an annual incidence of 4 cases per million per year.1 Most patients with insulinoma present with recurrent episodes of symptomatic hypoglycemia caused by a benign pancreatic tumor.1 Approximately 10% of insulinoma cases are malignant with a reported 10-year survival rate of less than 20%.2 Surgical excision of the tumor is the preferred and the most effective treatment option for benign insulinomas.3 Malignant and metastatic insulinomas are usually inoperable and present with intractable hypoglycemia requiring numerous therapeutic agents and often continuous dextrose infusion (Table 1). Recently, selective hepatic artery radioembolization with radioisotope Yttrium-90 (Y-90) has been reported to be beneficial to patients with malignant neuroendocrine tumors,4 but the experience with malignant insulinomas is very limited.5,6 Here, we report our experience with a case of metastatic malignant insulinoma with intractable hypoglycemia who was successfully treated with Y-90 therapy after failure to respond to conventional pancreatectomy and standard multiagent medical treatment.
CASE REPORTS Our case is a 56-year-old woman who was diagnosed with insulinoma in 2003. She underwent distal pancreatectomy and splenectomy shortly after the diagnosis. Two years later, hypoglycemia recurred, and imaging studies showed multiple liver metastases, proved by computed tomography (CT)-guided
biopsy to be neuroendocrine in origin. She was treated with hepatic chemoembolization (Eastern Cooperative Oncology Group 4298 including cisplatin, doxorubicin and mitomycin C), 8 cycles of capecitabine and 6 cycles of everolimus. However, a posttreatment abdominal CT scan showed progression of her liver metastasis, and she continued to suffer from frequent episodes of hypoglycemia despite octreotide, diazoxide and oral corticosteroid therapy. Therefore, she received 2 doses of 32.3 mCi of Y-90 into the hepatic artery with dramatic improvement in hypoglycemia, allowing discontinuation of diazoxide and corticosteroids without further episodes of hypoglycemia. Patient was re-admitted 11 months later with a blood glucose ⬍30 mg/dL and significantly elevated levels of proinsulin (1142.0 pmol/L), C-peptide (8.8 ng/mL) and insulin (25.8 IU/mL). Magnetic resonance imaging of abdomen showed diffuse hepatic metastases with multiple retroperitoneal and mesenteric lymph nodes. Repeat CT-guided biopsy of liver lesions was positive for markers of neuroendocrine differentiation including cytokeratin AE1/AE3, CD56, synaptophysin and chromogranin. Tumor localization single photon emission computed tomography with Indium-111 octreotide scan showed 1 focal area of avid uptake within the liver, and 24 hours single photon emission computed tomography CT images demonstrate multiple hypodense liver lesions. Patient was treated with increasing doses of diazoxide (200 mg twice daily), dexamethasone (4 mg twice daily), subcutaneous octreotide (300 mg thrice daily) and high-dose glucagon drip without improvement of hypoglycemic events requiring continuous dextrose infusion. Treatment with rapamycin and sunitinib was initiated but had to be stopped because of thrombocytopenia after 2 weeks. Because of the previous positive response to Y-90 radioembolization, a second dose of 27.0 mCi of Y-90 microspheres radioembolization was administered. She experienced resolution of hypoglycemic events and within 2 days, she was gradually weaned off glucagon and dextrose infusion. Three months later, she was readmitted again for hypoglycemia and received another Y-90 microspheres embolization. Hypoglycemia rapidly improved followed by sustained hyperglycemia despite discontinuation of diazoxide, corticosteroids and octreotide therapy over the course of a week. Time course of patient’s blood sugar is illustrated in Figure 1.
DISCUSSION From the Department of Medicine, Emory University School of Medicine, Atlanta, Georgia. Submitted April 5, 2010; accepted in revised form April 28, 2010. Correspondence: Guillermo E. Umpierrez, MD, Department of Medicine, Emory University School of Medicine, 49 Jesse Hill Jr Dr SE, Atlanta, GA 30303 (E-mail: [email protected]).
414
Hypoglycemia is one of the cardinal symptoms of malignant insulinoma and can be difficult to treat. Several drugs with different mechanism of action have been recommended for management of hypoglycemia in insulinoma patients (Table 1). Calcium channel blockers, phenytoin, diazoxide and octreotide are the most common medications given to treat hypo-
The American Journal of the Medical Sciences • Volume 340, Number 5, November 2010
Yttirum-90 in Malignant Insulinoma
TABLE 1. Available modalities for treatment of hypoglycemia in patients with insulinoma Mechanism of action Inhibitors of insulin secretion Diazoxide
Side effects
Dosage
Comments
300–600 mg (or 3 mg to 8 mg/kg) daily orally in 2 or 3 divided doses 50–2000 g/d
Effective in ⬎50% of insulinoma cases. Lower success with malignant insulinoma Effective in ⬎50% of insulinoma cases. Limited response with malignant insulinoma More than 50% biochemical response rate; limited tumor response rate More than 50% biochemical response rate; limited tumor response rate Temporary effect; limited experience
Inhibition of insulin release by blockade of ATPrelated potassium channels
Sodium retention and edema
Diarrhea, bradycardia and gall stone formation
Sandostatin LAR
Somatostatin analogue, inhibition of insulin release by acting on somatostatin receptors Same as octreotide
Same as octreotide
20 mg monthly
Lanreotide
Same as octreotide
Same as octreotide
30 mg every other week
Verapamil
Inhibition of insulin release
240–480 mg/d in 3–4 divided doses
Phenytoin
Inhibition of insulin release
Glucocorticoids
Inhibit insulin production and increase peripheral resistance to insulin
Constipation, hypotension and peripheral edema Gingival hypertrophy, ataxia, slurred speech and rashes Osteoporosis and immunosuppression
Octreotide
Chemotherapeutic agents Everolimus and rapamycin
400 mg/d
Temporary effect; limited experience
Up to 60 mg of prednisone or its equivalent dose of other forms of glucocorticoids
Effective in 30% of benign insulinomas; limited experience with malignant insulinoma
Thrombocytopenia, stomatitis, fatigue and water retention
Everolimus 5 mg/d; rapamycin 2 mg/d
Nausea, vomiting and nephrotoxicity
1–1.5 g weekly
Case reports and small case series of success in controlling hypoglycemia Response rates ⬃60% when used in combination with 5fluorouracil (5-FU) or doxorubicin Reported success rate ⬃30% when used in combination with streptozocin, doxorubicin and cyclophosphamide Variable response rate when used in combination with other chemotherapeutic agents Partial response rate of 32%–90%; complete response of 2%–18%
Streptozocin
Antagonists of mTOR, hepatic and peripheral resistance to insulin and beta islet cell toxicity Cell toxicity
Fluorouracil (5-FU)
Cell toxicity
Vomiting, mucositis, phlebitis and leucopenia
400 mg/m2
Doxorubicin
Cell toxicity
Nausea, vomiting, neutropenia and dilated cardiomyopathy
60 mg/m2
Radioembolization
Cell toxicity
Radiation toxicity, liver failure and gastritis
Variable
mTOR, mammalian target of rapamycin.
glycemia; however, these medications provide temporary relief, and long-term treatment requires treating the underlying disease. Various antitumor treatments such as hepatic arterial embolization, chemoembolization or chemotherapy have been used with mixed success rates.7 Streptozotocin injection has been used with variable results in malignant insulinoma cases, decreasing tumor size in 30% to 70% of patients.8 –11 Higher success rates have been shown when streptozotocin is used in © 2010 Lippincott Williams & Wilkins
combination with another chemotherapeutic agent such as doxorubicin.8 –11 The use of mammalian target of rapamycin receptor inhibitors rapamycin and everolimus have been recently shown to significantly reduce hypoglycemic events12,13 and to reduce tumor burden in patients with insulinoma. Rapamycin (sirolimus) or its derivative everolimus are mammalian target of rapamycin receptor antagonists used to prevent organ trans-
415
Chandra et al
FIGURE 1. Time course of treatment with different modalities for the patient with insulinoma. She was treated with several methods of treatment including surgery, chemoembolization, chemotherapy and octreotide. Despite all these therapies, she was suffering from recurrent hypoglycemia. Four doses of radioembolization with Y-90 provided symptomatic relief for this patient. She was hyperglycemic at the time of discharge from last hospitalization.
plant rejection and cellular proliferation in drug-eluting coronary stents. These agents cause hyperglycemia by inducing hepatic and peripheral resistance to insulin and causing beta islet cell toxicity.14 It has been reported that everolimus can result in a median progression-free survival of 50 weeks in patients with islet cell carcinoma and also can improve hypoglycemia of the patients by decreasing production of insulin in beta cells. This effect is suggested to be conveyed through AMPK/JNK/FoxO pathway.15–18 A recent open-label phase II study demonstrated that everolimus (10 mg daily) has radiological antitumor effect in patients with progressive metastatic pancreatic neuroendocrine tumors despite chemotherapy.19 This patient failed to respond to therapy with everolimus and rapamycin without improvement of hypoglycemic events or in reducing tumor size. The overexpression of somatostatin receptors in a variety of neuroendocrine tumors including insulinomas has allowed the use of somatostatin receptor targeting for both diagnostic and therapeutic purposes in many of these tumors.20 Targeted radiotherapy of tumors expressing somatostatin receptors in high amounts is an advanced example of using the high expression of somatostatin receptors.21 In animal studies, complete tumor destruction has been achieved, especially of smaller neuroendocrine pancreatic tumors, by using the somatostatin receptor Y-90 as radiotracer.22 In patients with metastatic disease, radiolabeled somatostatin analogue therapy with Indium-111 has been shown to have a 20% to 30% response rate.23 Recently, a report of 2 cases treated with octreotide radiolabeled with Lutetium-177 also reported success in reducing the tumor burden and in resolution of hypoglycemic events.6 Although several studies have shown that radioembolization with Y-90-microsphere embolization is effective in improving survival in patients with metastatic colorectal cancer and hepatocellular tumors,24 there are few studies investigating the use of Y-90 in metastatic neuroendocrine tumors.4,25–27 In these studies, the overall response rate has been reported to be between 32% and 90%, with median survival of 15 to 70 months. Kennedy et al,4 in a multicenter study in 148 patients
416
treated with Y-90 microsphere embolization reported partial tumor regression in 60.5% of patients and complete regression in 2.7% of patients. No significant radiation toxicity was reported, and the median survival was 70 months. However, their study included only 3 cases of insulinoma, and the outcome was not separately reported for insulinoma cases. In a study by King et al,26 among 34 cases with metastatic pancreatic neuroendocrine tumors but none with insulinoma, radiologic evidence of partial or complete tumor regression was reported in 32% and 18% of patients, respectively, with median survival rate of 29 months. Rhee et al27 reported 42 cases, 11 of them with pancreatic neuroendocrine tumors as origin of metastases to liver, with a very high response rate (92%)24. Sato et al reported 225 patients with liver metastases from various sites of origin (colorectal, breast and pancreas) among which 19 were neuroendocrine tumors. They reported radiologic evidence for tumor regression in 43% of cases with 2% complete regression; however, only 6 of these patients had a pancreatic tumor as an origin of the metastases, and there were no reported cases of insulinoma. We present our experience in treating a patient with malignant metastatic insulinoma with Y-90 microspheres radioembolization that resulted in resolution of the intractable hypoglycemia for approximately 16 months after each treatment, allowing discontinuation of dextrose infusion and hospital discharge. However, the effect of Y-90 administration was transient and without evidence of tumor shrinkage in imaging studies. In summary, this case illustrates difficulties in the management of hypoglycemia in patients with metastatic insulinoma. Despite using multiple conventional medical therapies for glycemic control (diazoxide, octreotide and chemotherapeutic agents), hypoglycemia persisted and required frequent admissions to receive intravenous dextrose infusion. We have shown that Y-90 administration results in transient resolution of intractable hypoglycemia owing to malignant insulinoma. Randomized-controlled studies are needed to determine safety and efficacy of Y-90 in the management of malignant insulinoma-induced hypoglycemia. Volume 340, Number 5, November 2010
Yttirum-90 in Malignant Insulinoma
REFERENCES 1. Kaltsas GA, Besser GM, Grossman AB. The diagnosis and medical management of advanced neuroendocrine tumors. Endocr Rev 2004; 25:458 –511.
14. Crutchlow MF, Bloom RD. Transplant-associated hyperglycemia: a new look at an old problem. Clin J Am Soc Nephrol 2007;2:343–55. 15. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell 2006;124:471– 84.
2. Starke A, Saddig C, Mansfeld L, et al. Malignant metastatic insulinoma-postoperative treatment and follow-up. World J Surg 2005;29: 789 –93.
16. Bussiere CT, Lakey JR, Shapiro AM, et al. The impact of the mTOR inhibitor sirolimus on the proliferation and function of pancreatic islets and ductal cells. Diabetologia 2006;49:2341–9.
3. Tucker ON, Crotty PL, Conlon KC. The management of insulinoma. Br J Surg 2006;93:264 –75.
17. Fraenkel M, Ketzinel-Gilad M, Ariav Y, et al. mTOR inhibition by rapamycin prevents beta-cell adaptation to hyperglycemia and exacerbates the metabolic state in type 2 diabetes. Diabetes 2008;57:945–57.
4. Kennedy AS, Dezarn WA, McNeillie P, et al. Radioembolization for unresectable neuroendocrine hepatic metastases using resin 90Y-microspheres: early results in 148 patients. Am J Clin Oncol 2008;31:271–9. 5. Ho KW, Wong CC, Balalla B, et al. Malignant insulinomas with hepatic metastases successfully treated with selective internal radiation therapy. Clin Endocrinol (Oxf) 2006;65:410 –1. 6. Ong G, Henley D, Hurley D, et al. Therapies for the medical management of persistent hypoglycaemia in two cases of inoperable malignant insulinoma. Eur J Endocrinol 2010;162:1001– 8. 7. Nakakura EK, Bergsland EK. Islet cell carcinoma: neuroendocrine tumors of the pancreas and periampullary region. Hematol Oncol Clin North Am 2007;21:457–73, viii. 8. Moertel CG, Lefkopoulo M, Lipsitz S, et al. Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med 1992;326:519 –23. 9. Cheng PN, Saltz LB. Failure to confirm major objective antitumor activity for streptozocin and doxorubicin in the treatment of patients with advanced islet cell carcinoma. Cancer 1999;86:944 – 8. 10. Rivera E, Ajani JA. Doxorubicin, streptozocin, and 5-fluorouracil chemotherapy for patients with metastatic islet-cell carcinoma. Am J Clin Oncol 1998;21:36 – 8. 11. Kouvaraki MA, Ajani AJ, Hoff P, et al. Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas. J Clin Oncol 2004;22: 4762–71. 12. Kulke MH, Bergsland EK, Yao JC. Glycemic control in patients with insulinoma treated with everolimus. N Engl J Med 2009;360:195–7. 13. Bourcier ME, Sherrod A, DiGuardo M, et al. Successful control of intractable hypoglycemia using rapamycin in an 86-year-old man with a pancreatic insulin-secreting islet cell tumor and metastases. J Clin Endocrinol Metab 2009;94:3157– 62.
© 2010 Lippincott Williams & Wilkins
18. Yao JC, Phan AT, Chang DZ, et al. Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. J Clin Oncol 2008;26: 4311– 8. 19. Yao JC, Lombard-Bohas C, Baudin E, et al. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol 2010;28:69 –76. 20. Modlin IM, Oberg K, Chung DC, et al. Gastroenteropancreatic neuroendocrine tumours. Lancet Oncol 2008;9:61–72. 21. Reubi JC. Peptide receptor expression in GEP-NET. Virchows Arch 2007;451(suppl 1):S47–50. 22. Stolz B, Weckbecker G, Smith-Jones PM, et al. The somatostatin receptor-targeted radiotherapeutic [90Y-DOTA-DPhe1, Tyr3]octreotide (90Y-SMT 487) eradicates experimental rat pancreatic CA 20948 tumours. Eur J Nucl Med 1998;25:668 –74. 23. Kwekkeboom DJ, Mueller-Brand J, Paganelli G, et al. Overview of results of peptide receptor radionuclide therapy with 3 radiolabeled somatostatin analogs. J Nucl Med 2005;46(suppl 1):62S– 6S. 24. Sato KT, Lewandowski RJ, Mulcahy MF, et al. Unresectable chemorefractory liver metastases: radioembolization with 90Y microspheres—safety, efficacy, and survival. Radiology 2008;247:507–15. 25. Andrews JC, Walker SC, Ackermann RJ, et al. Hepatic radioembolization with yttrium-90 containing glass microspheres: preliminary results and clinical follow-up. J Nucl Med 1994;35:1637– 44. 26. King J, Quinn R, Glenn DM, et al. Radioembolization with selective internal radiation microspheres for neuroendocrine liver metastases. Cancer 2008;113:921–9. 27. Rhee TK, Lewandowski RJ, Liu DM, et al. 90Y Radioembolization for metastatic neuroendocrine liver tumors: preliminary results from a multi-institutional experience. Ann Surg 2008;247:1029 –35.
417
Management of Intractable Hypoglycemia With Yttirum-90 Radioembolization in a Patient With Malignant Insulinoma Prakash Chandra, MD, Shadi Sadeghi Yarandi, MD, Natasha Khazai, MD, Sol Jacobs, MD and Guillermo E. Umpierrez, MD
Abstract: Metastatic insulinomas may present with recurrent lifethreatening hypoglycemia. Treatment of hypoglycemia in such patients is difficult and frequently fails to respond to numerous therapeutic agents, requiring continuous dextrose infusion. The authors present our experience with Yttirum-90 radioembolization in a patient with metastatic malignant insulinoma who failed to respond to distal pancreatectomy, systemic chemotherapy with capecitabine and everolimus and medical treatment with somatostatin analogues, diazoxide and corticosteroids. Treatment with repeated Y-90 radioembolization resulted in rapid resolution of hypoglycemic events, allowing discontinuation of dextrose infusion and hospital discharge. However, the effect of Y-90 administration seems to be transient and without evidence of tumor shrinkage in imaging studies. Key Indexing Terms: Insulinoma; Hypoglycemia; Malignant insulinoma; Yttirum-90; Octreotide therapy. [Am J Med Sci 2010;340(5):414–417.]
I
nsulinoma is a rare islet cell tumor of pancreas with an annual incidence of 4 cases per million per year.1 Most patients with insulinoma present with recurrent episodes of symptomatic hypoglycemia caused by a benign pancreatic tumor.1 Approximately 10% of insulinoma cases are malignant with a reported 10-year survival rate of less than 20%.2 Surgical excision of the tumor is the preferred and the most effective treatment option for benign insulinomas.3 Malignant and metastatic insulinomas are usually inoperable and present with intractable hypoglycemia requiring numerous therapeutic agents and often continuous dextrose infusion (Table 1). Recently, selective hepatic artery radioembolization with radioisotope Yttrium-90 (Y-90) has been reported to be beneficial to patients with malignant neuroendocrine tumors,4 but the experience with malignant insulinomas is very limited.5,6 Here, we report our experience with a case of metastatic malignant insulinoma with intractable hypoglycemia who was successfully treated with Y-90 therapy after failure to respond to conventional pancreatectomy and standard multiagent medical treatment.
CASE REPORTS Our case is a 56-year-old woman who was diagnosed with insulinoma in 2003. She underwent distal pancreatectomy and splenectomy shortly after the diagnosis. Two years later, hypoglycemia recurred, and imaging studies showed multiple liver metastases, proved by computed tomography (CT)-guided
biopsy to be neuroendocrine in origin. She was treated with hepatic chemoembolization (Eastern Cooperative Oncology Group 4298 including cisplatin, doxorubicin and mitomycin C), 8 cycles of capecitabine and 6 cycles of everolimus. However, a posttreatment abdominal CT scan showed progression of her liver metastasis, and she continued to suffer from frequent episodes of hypoglycemia despite octreotide, diazoxide and oral corticosteroid therapy. Therefore, she received 2 doses of 32.3 mCi of Y-90 into the hepatic artery with dramatic improvement in hypoglycemia, allowing discontinuation of diazoxide and corticosteroids without further episodes of hypoglycemia. Patient was re-admitted 11 months later with a blood glucose ⬍30 mg/dL and significantly elevated levels of proinsulin (1142.0 pmol/L), C-peptide (8.8 ng/mL) and insulin (25.8 IU/mL). Magnetic resonance imaging of abdomen showed diffuse hepatic metastases with multiple retroperitoneal and mesenteric lymph nodes. Repeat CT-guided biopsy of liver lesions was positive for markers of neuroendocrine differentiation including cytokeratin AE1/AE3, CD56, synaptophysin and chromogranin. Tumor localization single photon emission computed tomography with Indium-111 octreotide scan showed 1 focal area of avid uptake within the liver, and 24 hours single photon emission computed tomography CT images demonstrate multiple hypodense liver lesions. Patient was treated with increasing doses of diazoxide (200 mg twice daily), dexamethasone (4 mg twice daily), subcutaneous octreotide (300 mg thrice daily) and high-dose glucagon drip without improvement of hypoglycemic events requiring continuous dextrose infusion. Treatment with rapamycin and sunitinib was initiated but had to be stopped because of thrombocytopenia after 2 weeks. Because of the previous positive response to Y-90 radioembolization, a second dose of 27.0 mCi of Y-90 microspheres radioembolization was administered. She experienced resolution of hypoglycemic events and within 2 days, she was gradually weaned off glucagon and dextrose infusion. Three months later, she was readmitted again for hypoglycemia and received another Y-90 microspheres embolization. Hypoglycemia rapidly improved followed by sustained hyperglycemia despite discontinuation of diazoxide, corticosteroids and octreotide therapy over the course of a week. Time course of patient’s blood sugar is illustrated in Figure 1.
DISCUSSION From the Department of Medicine, Emory University School of Medicine, Atlanta, Georgia. Submitted April 5, 2010; accepted in revised form April 28, 2010. Correspondence: Guillermo E. Umpierrez, MD, Department of Medicine, Emory University School of Medicine, 49 Jesse Hill Jr Dr SE, Atlanta, GA 30303 (E-mail: [email protected]).
414
Hypoglycemia is one of the cardinal symptoms of malignant insulinoma and can be difficult to treat. Several drugs with different mechanism of action have been recommended for management of hypoglycemia in insulinoma patients (Table 1). Calcium channel blockers, phenytoin, diazoxide and octreotide are the most common medications given to treat hypo-
The American Journal of the Medical Sciences • Volume 340, Number 5, November 2010
Yttirum-90 in Malignant Insulinoma
TABLE 1. Available modalities for treatment of hypoglycemia in patients with insulinoma Mechanism of action Inhibitors of insulin secretion Diazoxide
Side effects
Dosage
Comments
300–600 mg (or 3 mg to 8 mg/kg) daily orally in 2 or 3 divided doses 50–2000 g/d
Effective in ⬎50% of insulinoma cases. Lower success with malignant insulinoma Effective in ⬎50% of insulinoma cases. Limited response with malignant insulinoma More than 50% biochemical response rate; limited tumor response rate More than 50% biochemical response rate; limited tumor response rate Temporary effect; limited experience
Inhibition of insulin release by blockade of ATPrelated potassium channels
Sodium retention and edema
Diarrhea, bradycardia and gall stone formation
Sandostatin LAR
Somatostatin analogue, inhibition of insulin release by acting on somatostatin receptors Same as octreotide
Same as octreotide
20 mg monthly
Lanreotide
Same as octreotide
Same as octreotide
30 mg every other week
Verapamil
Inhibition of insulin release
240–480 mg/d in 3–4 divided doses
Phenytoin
Inhibition of insulin release
Glucocorticoids
Inhibit insulin production and increase peripheral resistance to insulin
Constipation, hypotension and peripheral edema Gingival hypertrophy, ataxia, slurred speech and rashes Osteoporosis and immunosuppression
Octreotide
Chemotherapeutic agents Everolimus and rapamycin
400 mg/d
Temporary effect; limited experience
Up to 60 mg of prednisone or its equivalent dose of other forms of glucocorticoids
Effective in 30% of benign insulinomas; limited experience with malignant insulinoma
Thrombocytopenia, stomatitis, fatigue and water retention
Everolimus 5 mg/d; rapamycin 2 mg/d
Nausea, vomiting and nephrotoxicity
1–1.5 g weekly
Case reports and small case series of success in controlling hypoglycemia Response rates ⬃60% when used in combination with 5fluorouracil (5-FU) or doxorubicin Reported success rate ⬃30% when used in combination with streptozocin, doxorubicin and cyclophosphamide Variable response rate when used in combination with other chemotherapeutic agents Partial response rate of 32%–90%; complete response of 2%–18%
Streptozocin
Antagonists of mTOR, hepatic and peripheral resistance to insulin and beta islet cell toxicity Cell toxicity
Fluorouracil (5-FU)
Cell toxicity
Vomiting, mucositis, phlebitis and leucopenia
400 mg/m2
Doxorubicin
Cell toxicity
Nausea, vomiting, neutropenia and dilated cardiomyopathy
60 mg/m2
Radioembolization
Cell toxicity
Radiation toxicity, liver failure and gastritis
Variable
mTOR, mammalian target of rapamycin.
glycemia; however, these medications provide temporary relief, and long-term treatment requires treating the underlying disease. Various antitumor treatments such as hepatic arterial embolization, chemoembolization or chemotherapy have been used with mixed success rates.7 Streptozotocin injection has been used with variable results in malignant insulinoma cases, decreasing tumor size in 30% to 70% of patients.8 –11 Higher success rates have been shown when streptozotocin is used in © 2010 Lippincott Williams & Wilkins
combination with another chemotherapeutic agent such as doxorubicin.8 –11 The use of mammalian target of rapamycin receptor inhibitors rapamycin and everolimus have been recently shown to significantly reduce hypoglycemic events12,13 and to reduce tumor burden in patients with insulinoma. Rapamycin (sirolimus) or its derivative everolimus are mammalian target of rapamycin receptor antagonists used to prevent organ trans-
415
Chandra et al
FIGURE 1. Time course of treatment with different modalities for the patient with insulinoma. She was treated with several methods of treatment including surgery, chemoembolization, chemotherapy and octreotide. Despite all these therapies, she was suffering from recurrent hypoglycemia. Four doses of radioembolization with Y-90 provided symptomatic relief for this patient. She was hyperglycemic at the time of discharge from last hospitalization.
plant rejection and cellular proliferation in drug-eluting coronary stents. These agents cause hyperglycemia by inducing hepatic and peripheral resistance to insulin and causing beta islet cell toxicity.14 It has been reported that everolimus can result in a median progression-free survival of 50 weeks in patients with islet cell carcinoma and also can improve hypoglycemia of the patients by decreasing production of insulin in beta cells. This effect is suggested to be conveyed through AMPK/JNK/FoxO pathway.15–18 A recent open-label phase II study demonstrated that everolimus (10 mg daily) has radiological antitumor effect in patients with progressive metastatic pancreatic neuroendocrine tumors despite chemotherapy.19 This patient failed to respond to therapy with everolimus and rapamycin without improvement of hypoglycemic events or in reducing tumor size. The overexpression of somatostatin receptors in a variety of neuroendocrine tumors including insulinomas has allowed the use of somatostatin receptor targeting for both diagnostic and therapeutic purposes in many of these tumors.20 Targeted radiotherapy of tumors expressing somatostatin receptors in high amounts is an advanced example of using the high expression of somatostatin receptors.21 In animal studies, complete tumor destruction has been achieved, especially of smaller neuroendocrine pancreatic tumors, by using the somatostatin receptor Y-90 as radiotracer.22 In patients with metastatic disease, radiolabeled somatostatin analogue therapy with Indium-111 has been shown to have a 20% to 30% response rate.23 Recently, a report of 2 cases treated with octreotide radiolabeled with Lutetium-177 also reported success in reducing the tumor burden and in resolution of hypoglycemic events.6 Although several studies have shown that radioembolization with Y-90-microsphere embolization is effective in improving survival in patients with metastatic colorectal cancer and hepatocellular tumors,24 there are few studies investigating the use of Y-90 in metastatic neuroendocrine tumors.4,25–27 In these studies, the overall response rate has been reported to be between 32% and 90%, with median survival of 15 to 70 months. Kennedy et al,4 in a multicenter study in 148 patients
416
treated with Y-90 microsphere embolization reported partial tumor regression in 60.5% of patients and complete regression in 2.7% of patients. No significant radiation toxicity was reported, and the median survival was 70 months. However, their study included only 3 cases of insulinoma, and the outcome was not separately reported for insulinoma cases. In a study by King et al,26 among 34 cases with metastatic pancreatic neuroendocrine tumors but none with insulinoma, radiologic evidence of partial or complete tumor regression was reported in 32% and 18% of patients, respectively, with median survival rate of 29 months. Rhee et al27 reported 42 cases, 11 of them with pancreatic neuroendocrine tumors as origin of metastases to liver, with a very high response rate (92%)24. Sato et al reported 225 patients with liver metastases from various sites of origin (colorectal, breast and pancreas) among which 19 were neuroendocrine tumors. They reported radiologic evidence for tumor regression in 43% of cases with 2% complete regression; however, only 6 of these patients had a pancreatic tumor as an origin of the metastases, and there were no reported cases of insulinoma. We present our experience in treating a patient with malignant metastatic insulinoma with Y-90 microspheres radioembolization that resulted in resolution of the intractable hypoglycemia for approximately 16 months after each treatment, allowing discontinuation of dextrose infusion and hospital discharge. However, the effect of Y-90 administration was transient and without evidence of tumor shrinkage in imaging studies. In summary, this case illustrates difficulties in the management of hypoglycemia in patients with metastatic insulinoma. Despite using multiple conventional medical therapies for glycemic control (diazoxide, octreotide and chemotherapeutic agents), hypoglycemia persisted and required frequent admissions to receive intravenous dextrose infusion. We have shown that Y-90 administration results in transient resolution of intractable hypoglycemia owing to malignant insulinoma. Randomized-controlled studies are needed to determine safety and efficacy of Y-90 in the management of malignant insulinoma-induced hypoglycemia. Volume 340, Number 5, November 2010
Yttirum-90 in Malignant Insulinoma
REFERENCES 1. Kaltsas GA, Besser GM, Grossman AB. The diagnosis and medical management of advanced neuroendocrine tumors. Endocr Rev 2004; 25:458 –511.
14. Crutchlow MF, Bloom RD. Transplant-associated hyperglycemia: a new look at an old problem. Clin J Am Soc Nephrol 2007;2:343–55. 15. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell 2006;124:471– 84.
2. Starke A, Saddig C, Mansfeld L, et al. Malignant metastatic insulinoma-postoperative treatment and follow-up. World J Surg 2005;29: 789 –93.
16. Bussiere CT, Lakey JR, Shapiro AM, et al. The impact of the mTOR inhibitor sirolimus on the proliferation and function of pancreatic islets and ductal cells. Diabetologia 2006;49:2341–9.
3. Tucker ON, Crotty PL, Conlon KC. The management of insulinoma. Br J Surg 2006;93:264 –75.
17. Fraenkel M, Ketzinel-Gilad M, Ariav Y, et al. mTOR inhibition by rapamycin prevents beta-cell adaptation to hyperglycemia and exacerbates the metabolic state in type 2 diabetes. Diabetes 2008;57:945–57.
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