Difference between revisions of "Neuroendocrine tumor"
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'''There is limited and controversial clinical trial information about adjuvant mitotane use. See the references for additional case series and expert recommendation articles.''' | '''There is limited and controversial clinical trial information about adjuvant mitotane use. See the references for additional case series and expert recommendation articles.''' | ||
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EDP: '''<u>E</u>'''toposide, '''<u>D</u>'''oxorubicin, '''<u>P</u>'''latinol (Cisplatin) | EDP: '''<u>E</u>'''toposide, '''<u>D</u>'''oxorubicin, '''<u>P</u>'''latinol (Cisplatin) | ||
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===Regimen #1 {{#subobject:867317|Variant=1}}=== | ===Regimen #1 {{#subobject:867317|Variant=1}}=== | ||
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===Regimen {{#subobject:cd8cf6|Variant=1}}=== | ===Regimen {{#subobject:cd8cf6|Variant=1}}=== | ||
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===Regimen #1 {{#subobject:b0f62f|Variant=1}}=== | ===Regimen #1 {{#subobject:b0f62f|Variant=1}}=== | ||
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FAS: '''<u>F</u>'''luorouracil, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>S</u>'''treptozocin | FAS: '''<u>F</u>'''luorouracil, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>S</u>'''treptozocin | ||
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CVD: '''<u>C</u>'''yclophosphamide, '''<u>V</u>'''incristine, '''<u>D</u>'''acarbazine | CVD: '''<u>C</u>'''yclophosphamide, '''<u>V</u>'''incristine, '''<u>D</u>'''acarbazine |
Revision as of 04:12, 24 October 2016
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Is there a regimen missing from this list? Would you like to share a different dosage/schedule or an additional reference for a regimen? Have you noticed an error? Do you have an idea that will help the site grow to better meet your needs and the needs of many others? You are invited to contribute to the site.
14 regimens on this page
20 variants on this page
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Adrenal gland tumors, adrenocortical carcinoma - adjuvant therapy
Mitotane (Lysodren)
back to top |
There is limited and controversial clinical trial information about adjuvant mitotane use. See the references for additional case series and expert recommendation articles.
Regimen #1
Study | Evidence |
Wängberg et al. 2010 | Phase II |
Patients started on adjuvant mitotane within 4 weeks of their surgical resection.
Chemotherapy
- Mitotane (Lysodren) 2000 mg PO per day (frequency not specified, such as whether the total daily dose was divided into a few doses throughout the day); within the first 2 to 3 months, dose was adjusted to achieve a target therapeutic drug level of 14 to 20 mg/L
2 to 3-year course
Regimen #2
Study | Evidence |
Haak et al. 1994 | Phase II |
Haak et al. 1994 concluded that "mitotane treatment in adrenocortical carcinoma is effective only when high serum levels [trough of at least 14 mg/L] can be achieved."
Chemotherapy
- Mitotane (Lysodren) 1000 to 2000 mg PO QID (total dose per day: 4000 to 8000 mg), with target mitotane trough of above 14 mg/L
Supportive medications
- Hydrocortisone (Cortef) 30 to 120 mg per day or Fludrocortisone (Florinef) 0.1 to 0.4 mg per day
- Metoclopramide (Reglan) prn "gastrointestinal side-effects"
- Loperamide (Imodium) prn "gastrointestinal side-effects"
2-year course "if resection was judged to be complete or for 1 year after apparent disappearance of the tumour"
References
- Vassilopoulou-Sellin R, Guinee VF, Klein MJ, Taylor SH, Hess KR, Schultz PN, Samaan NA. Impact of adjuvant mitotane on the clinical course of patients with adrenocortical cancer. Cancer. 1993 May 15;71(10):3119-23. link to original article PubMed
- Haak HR, Hermans J, van de Velde CJ, Lentjes EG, Goslings BM, Fleuren GJ, Krans HM. Optimal treatment of adrenocortical carcinoma with mitotane: results in a consecutive series of 96 patients. Br J Cancer. 1994 May;69(5):947-51. link to PMC article contains verified protocol PubMed content property of HemOnc.org
- Terzolo M, Angeli A, Fassnacht M, Daffara F, Tauchmanova L, Conton PA, Rossetto R, Buci L, Sperone P, Grossrubatscher E, Reimondo G, Bollito E, Papotti M, Saeger W, Hahner S, Koschker AC, Arvat E, Ambrosi B, Loli P, Lombardi G, Mannelli M, Bruzzi P, Mantero F, Allolio B, Dogliotti L, Berruti A. Adjuvant mitotane treatment for adrenocortical carcinoma. N Engl J Med. 2007 Jun 7;356(23):2372-80. link to original article PubMed
- Veytsman I, Nieman L, Fojo T. Management of endocrine manifestations and the use of mitotane as a chemotherapeutic agent for adrenocortical carcinoma. J Clin Oncol. 2009 Sep 20;27(27):4619-29. Epub 2009 Aug 10. link to original article PubMed
- Wängberg B, Khorram-Manesh A, Jansson S, Nilsson B, Nilsson O, Jakobsson CE, Lindstedt S, Odén A, Ahlman H. The long-term survival in adrenocortical carcinoma with active surgical management and use of monitored mitotane. Endocr Relat Cancer. 2010 Feb 18;17(1):265-72. Print 2010 Mar. link to original article contains verified protocol PubMed
Mitotane & Streptozocin
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Regimen
Study | Evidence |
Khan et al. 2010 | Phase II |
Induction course
- Streptozocin (Zanosar) 1000 mg IV once per day on days 1 to 5
5-day course, followed by main regimen
Main regimen
- Mitotane (Lysodren) 1000 to 4000 mg/day PO; daily dose is taken in 2 to 3 divided doses per day
- Streptozocin (Zanosar) 2000 mg IV once per day on days 1 to 5
Supportive medications
- 5-HT3 antagonists prior to streptozocin
- Hydrocortisone (Cortef) 25 to 100 mg/day
21-day cycles; duration of therapy not clearly specified
References
- Khan TS, Imam H, Juhlin C, Skogseid B, Gröndal S, Tibblin S, Wilander E, Oberg K, Eriksson B. Streptozocin and o,p'DDD in the treatment of adrenocortical cancer patients: long-term survival in its adjuvant use. Ann Oncol. 2000 Oct;11(10):1281-7. link to original article contains verified protocol PubMed
Adrenal gland tumors, adrenocortical carcinoma - recurrent, locally advanced, or metastatic disease
Mitotane (Lysodren)
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Regimen
Study | Evidence |
Veytsman et al. 2009 | Review |
Chemotherapy
- Mitotane (Lysodren) 1000 to 2000 mg PO per day (frequency not specified, such as whether the total daily dose was divided into a few doses throughout the day); then increase daily dose of Mitotane (Lysodren) by 1000 to 2000 mg every 1 to 2 weeks to the maximum tolerated dose, not to exceed 6000 mg ("never > 6 to 10 g/d"). Target mitotane drug level is 10 to 14 mg/L.
References
- Review: Veytsman I, Nieman L, Fojo T. Management of endocrine manifestations and the use of mitotane as a chemotherapeutic agent for adrenocortical carcinoma. J Clin Oncol. 2009 Sep 20;27(27):4619-29. Epub 2009 Aug 10. link to original article contains verified protocol PubMed
Mitotane & EDP
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EDP: Etoposide, Doxorubicin, Platinol (Cisplatin)
Regimen #1
Study | Evidence | Comparator | Efficacy |
Fassnacht et al. 2012 (FIRM-ACT) | Phase III | Mitotane & Streptozocin | Superior PFS |
Mitotane is started at least 1 week before the other chemotherapy; the rest of the therapy is as described below.
Chemotherapy
- Mitotane (Lysodren) on days 1 to 28, with target mitotane trough of 14 to 20 mg/L (initial dose and frequency not specified)
- Etoposide (Vepesid) 100 mg/m2 IV once per day on days 2 to 4
- Doxorubicin (Adriamycin) 40 mg/m2 IV once on day 1
- Cisplatin (Platinol) 40 mg/m2 IV once per day on days 3 & 4
Supportive medications
- Glucocorticoid replacement was recommended in all patients except those with persistent Cushing's syndrome.
28-day cycles
Regimen #2
Study | Evidence |
Berruti et al. 2005 | Phase II |
Chemotherapy
- Mitotane (Lysodren) 1000 mg PO per day (frequency not specified, such as whether the total daily dose was divided into a few doses throughout the day) on days 1 to 28; then dose is increased as tolerated up to 4000 mg/day or maximum tolerated dose
- Etoposide (Vepesid) 100 mg/m2 IV once per day on days 5 to 7
- Doxorubicin (Adriamycin) 20 mg/m2 IV once per day on days 1 & 8
- Cisplatin (Platinol) 40 mg/m2 IV once per day on days 2 & 9
28-day cycle for up to 6 cycles, given until progression of disease, unacceptable toxicity, or patient refusal
References
- Berruti A, Terzolo M, Sperone P, Pia A, Della Casa S, Gross DJ, Carnaghi C, Casali P, Porpiglia F, Mantero F, Reimondo G, Angeli A, Dogliotti L. Etoposide, doxorubicin and cisplatin plus mitotane in the treatment of advanced adrenocortical carcinoma: a large prospective phase II trial. Endocr Relat Cancer. 2005 Sep;12(3):657-66. link to original article contains verified protocol PubMed
- Fassnacht M, Terzolo M, Allolio B, Baudin E, Haak H, Berruti A, Welin S, Schade-Brittinger C, Lacroix A, Jarzab B, Sorbye H, Torpy DJ, Stepan V, Schteingart DE, Arlt W, Kroiss M, Leboulleux S, Sperone P, Sundin A, Hermsen I, Hahner S, Willenberg HS, Tabarin A, Quinkler M, de la Fouchardière C, Schlumberger M, Mantero F, Weismann D, Beuschlein F, Gelderblom H, Wilmink H, Sender M, Edgerly M, Kenn W, Fojo T, Müller HH, Skogseid B; FIRM-ACT Study Group. Combination chemotherapy in advanced adrenocortical carcinoma. N Engl J Med. 2012 Jun 7;366(23):2189-97. Epub 2012 May 2. link to original article contains verified protocol PubMed
Mitotane & Streptozocin
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Regimen
Study | Evidence | Comparator | Efficacy |
Fassnacht et al. 2012 (FIRM-ACT) | Phase III | Mitotane & EDP | Inferior PFS |
Mitotane is started at least 1 week before the other chemotherapy; the rest of the therapy is as described below.
Chemotherapy
- Mitotane (Lysodren) on days 1 to 21, with target mitotane trough of 14 to 20 mg/L (initial dose and frequency not specified)
- Streptozocin (Zanosar) 1000 mg IV once per day on days 1 to 5 of cycle 1; then Streptozocin (Zanosar) 2000 mg IV once on day 1 of cycles 2 and on
Supportive medications
- Glucocorticoid replacement was recommended in all patients except those with persistent Cushing's syndrome.
21-day cycles
References
- Fassnacht M, Terzolo M, Allolio B, Baudin E, Haak H, Berruti A, Welin S, Schade-Brittinger C, Lacroix A, Jarzab B, Sorbye H, Torpy DJ, Stepan V, Schteingart DE, Arlt W, Kroiss M, Leboulleux S, Sperone P, Sundin A, Hermsen I, Hahner S, Willenberg HS, Tabarin A, Quinkler M, de la Fouchardière C, Schlumberger M, Mantero F, Weismann D, Beuschlein F, Gelderblom H, Wilmink H, Sender M, Edgerly M, Kenn W, Fojo T, Müller HH, Skogseid B; FIRM-ACT Study Group. Combination chemotherapy in advanced adrenocortical carcinoma. N Engl J Med. 2012 Jun 7;366(23):2189-97. Epub 2012 May 2. link to original article contains verified protocol PubMed
Carcinoid tumors
Interferon alfa-2b (Intron-A)
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Regimen
Study | Evidence | Comparator | Efficacy |
Faiss et al. 2003 | Phase III | Lanreotide | Seems not superior |
Lanreotide & Interferon alfa-2b | Seems not superior |
Immunotherapy
- Interferon alfa-2b (Intron-A) 5 million units SC given once per day, 3 times per week
Given until progression of disease
Patients who progressed on monotherapy then received combination lanreotide & interferon alfa.
References
- Faiss S, Pape UF, Böhmig M, Dörffel Y, Mansmann U, Golder W, Riecken EO, Wiedenmann B; International Lanreotide and Interferon Alfa Study Group. Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors--the International Lanreotide and Interferon Alfa Study Group. J Clin Oncol. 2003 Jul 15;21(14):2689-96. link to original article contains verified protocol PubMed
Lanreotide (Somatuline)
back to top |
Regimen
Study | Evidence | Comparator | Efficacy |
Faiss et al. 2003 | Phase III | Interferon alfa-2b | Seems not superior |
Lanreotide & Interferon alfa-2b | Seems not superior |
Endocrine therapy
- Lanreotide (Somatuline) 1 mg SC TID
Given until progression of disease
Patients who progressed on monotherapy then received combination lanreotide & interferon alfa.
References
- Faiss S, Pape UF, Böhmig M, Dörffel Y, Mansmann U, Golder W, Riecken EO, Wiedenmann B; International Lanreotide and Interferon Alfa Study Group. Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors--the International Lanreotide and Interferon Alfa Study Group. J Clin Oncol. 2003 Jul 15;21(14):2689-96. link to original article contains verified protocol PubMed
Lanreotide & Interferon alfa-2b
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Regimen
Study | Evidence | Comparator | Efficacy |
Faiss et al. 2003 | Phase III | Interferon alfa-2b | Seems not superior |
Lanreotide | Seems not superior |
Endocrine & Immunotherapy
- Lanreotide (Somatuline) 1 mg SC TID
- Interferon alfa-2b (Intron-A) 5 million units SC given once per day, 3 times per week
References
- Faiss S, Pape UF, Böhmig M, Dörffel Y, Mansmann U, Golder W, Riecken EO, Wiedenmann B; International Lanreotide and Interferon Alfa Study Group. Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors--the International Lanreotide and Interferon Alfa Study Group. J Clin Oncol. 2003 Jul 15;21(14):2689-96. link to original article contains verified protocol PubMed
Octreotide (Sandostatin)
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Regimen #1
Study | Evidence |
Oberg et al. 2004 | Consensus guideline |
Endocrine therapy
- Octreotide (Sandostatin) 0.1 to 0.5 mg SC given 2 to 4 times per day, with dose increased by doubling the dose every 3 to 4 days as needed to control symptoms
- "A reasonable starting dose is" Octreotide (Sandostatin) 0.15 mg SC TID
Treatment continued indefinitely unless patients have unmanageable side-effects or insufficient control of symptoms
Regimen #2
Study | Evidence |
Kvols et al. 1986 | Phase II |
Endocrine therapy
- Octreotide (Sandostatin) 0.15 mg SC BID on days 1 & 2, then 0.15 mg TID on days 3 and on
"Treatment was continued for as long as a clinical improvement was maintained"
Regimen #3
Study | Evidence | Comparator | Efficacy |
Kölby et al. 2003 | Randomized Phase II | Octreotide & Interferon alfa | Inferior TTP |
Endocrine therapy
- Octreotide (Sandostatin) 0.1 mg SC BID; patients with persistent carcinoid symptoms could receive increased doses up to 0.2 mg SC TID
References
- Kvols LK, Moertel CG, O'Connell MJ, Schutt AJ, Rubin J, Hahn RG. Treatment of the malignant carcinoid syndrome. Evaluation of a long-acting somatostatin analogue. N Engl J Med. 1986 Sep 11;315(11):663-6. link to original article contains verified protocol PubMed
- Janson ET, Oberg K. Long-term management of the carcinoid syndrome. Treatment with octreotide alone and in combination with alpha-interferon. Acta Oncol. 1993;32(2):225-9. link to original article PubMed
- Brentjens R, Saltz L. Islet cell tumors of the pancreas: the medical oncologist's perspective. Surg Clin North Am. 2001 Jun;81(3):527-42. link to original article PubMed
- Kölby L, Persson G, Franzén S, Ahrén B. Randomized clinical trial of the effect of interferon alpha on survival in patients with disseminated midgut carcinoid tumours. Br J Surg. 2003 Jun;90(6):687-93. link to original article contains verified protocol PubMed
- Review: Oberg K, Kvols L, Caplin M, Delle Fave G, de Herder W, Rindi G, Ruszniewski P, Woltering EA, Wiedenmann B. Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system. Ann Oncol. 2004 Jun;15(6):966-73. link to original article contains verified protocol PubMed
Octreotide LAR (Sandostatin LAR)
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Regimen #1
Study | Evidence | Comparator | Efficacy |
Rinke et al. 2009 (PROMID) | Phase III | Placebo | Superior TTP |
Pavel et al. 2011 (RADIANT-2) | Phase III | Octreotide LAR & Everolimus | Seems to have inferior PFS |
Endocrine therapy
- Octreotide LAR (Sandostatin LAR) 30 mg IM once on day 1, with potentially higher doses if needed for symptom control
28-day cycles, given until progression of disease
Regimen #2
Study | Evidence |
Oberg et al. 2004 | Consensus guideline |
Endocrine therapy
- Octreotide LAR (Sandostatin LAR) 20 to 30 mg IM once on day 1, with potentially higher doses if needed for symptom control
- "As a general rule, if the total [octreotide] IR dose is 200 to 600 µg/day [0.2 to 0.6 mg/day], LAR 20 mg should be tried, and if total IR dose is 750 to 1500 µg/day [0.75 to 1.5 mg/day], LAR 30 mg should be tried."
- Octreotide (Sandostatin) (dose not specified) SC as needed for additional symptom control
28-day cycles; treatment continued indefinitely unless patients have unmanageable side-effects or insufficient control of symptoms
References
- Review: Oberg K, Kvols L, Caplin M, Delle Fave G, de Herder W, Rindi G, Ruszniewski P, Woltering EA, Wiedenmann B. Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system. Ann Oncol. 2004 Jun;15(6):966-73. link to original article contains verified protocol PubMed
- Rinke A, Müller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, Mayer C, Aminossadati B, Pape UF, Bläker M, Harder J, Arnold C, Gress T, Arnold R; PROMID Study Group. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 2009 Oct 1;27(28):4656-63. Epub 2009 Aug 24. link to original article contains verified protocol PubMed
- Pavel ME, Hainsworth JD, Baudin E, Peeters M, Hörsch D, Winkler RE, Klimovsky J, Lebwohl D, Jehl V, Wolin EM, Oberg K, Van Cutsem E, Yao JC; RADIANT-2 Study Group. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet. 2011 Dec 10;378(9808):2005-12. Epub 2011 Nov 25. link to original article contains verified protocol PubMed
Octreotide & Everolimus
back to top |
Regimen #1
Study | Evidence | Comparator | Efficacy |
Pavel et al. 2011 (RADIANT-2) | Phase III | Octreotide LAR | Seems to have superior PFS |
Endocrine & Chemotherapy
- Octreotide LAR (Sandostatin LAR) 30 mg IM once every 28 days
- Everolimus (Afinitor) 10 mg PO once per day
Given until progression of disease or unacceptable toxicity
Regimen #2
Study | Evidence |
Yao et al. 2008 | Phase II |
Note: Everolimus "dose of 10 mg was associated with superior PFS...however, the study was not prospectively powered for these comparisons. These analyses should be considered exploratory."
Endocrine & Chemotherapy
- Octreotide LAR (Sandostatin LAR) 30 mg IM once on day 1
- Everolimus (Afinitor) 5 or 10 mg PO once per day on days 1 to 28
28-day cycle for up to 12 cycles or until progression of disease, though treatment could be continued beyond this period if thought by the treating physician to be beneficial
References
- Yao JC, Phan AT, Chang DZ, Wolff RA, Hess K, Gupta S, Jacobs C, Mares JE, Landgraf AN, Rashid A, Meric-Bernstam F. 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 Sep 10;26(26):4311-8. link to original article contains verified protocol PubMed
- Pavel ME, Hainsworth JD, Baudin E, Peeters M, Hörsch D, Winkler RE, Klimovsky J, Lebwohl D, Jehl V, Wolin EM, Oberg K, Van Cutsem E, Yao JC; RADIANT-2 Study Group. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet. 2011 Dec 10;378(9808):2005-12. Epub 2011 Nov 25. link to original article contains verified protocol PubMed
Octreotide & Interferon alfa
back to top |
Regimen
Study | Evidence | Comparator | Efficacy |
Kölby et al. 2003 | Randomized Phase II | Octreotide LAR | Superior TTP |
Kölby et al. 2003 did not specifically say whether Interferon alfa-2b (Intron-A) or Interferon alfa-2a (Roferon-A) was used.
Endocrine & Immunotherapy
- Octreotide (Sandostatin) 0.1 mg SC BID; patients with persistent carcinoid symptoms could receive increased doses up to Octreotide (Sandostatin) 0.2 mg SC TID
- Interferon alfa-2b (Intron-A) 3 million units (route not specified) given once per day, 3 days per week; increased as needed based on symptoms up to Interferon alfa-2b (Intron-A) 5 million units (route not specified) given once per day, 5 days per week
References
- Janson ET, Oberg K. Long-term management of the carcinoid syndrome. Treatment with octreotide alone and in combination with alpha-interferon. Acta Oncol. 1993;32(2):225-9. link to original article PubMed
- Kölby L, Persson G, Franzén S, Ahrén B. Randomized clinical trial of the effect of interferon alpha on survival in patients with disseminated midgut carcinoid tumours. Br J Surg. 2003 Jun;90(6):687-93. link to original article contains verified protocol PubMed
Placebo
back to top |
Regimen
Study | Evidence | Comparator | Efficacy |
Rinke et al. 2009 (PROMID) | Phase III | Octreotide LAR | Inferior TTP |
No active antineoplastic treatment. Used as a comparator arm and here for reference purposes only.
References
- Rinke A, Müller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, Mayer C, Aminossadati B, Pape UF, Bläker M, Harder J, Arnold C, Gress T, Arnold R; PROMID Study Group. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 2009 Oct 1;27(28):4656-63. Epub 2009 Aug 24. link to original article contains verified protocol PubMed
Temozolomide (Temodar)
back to top |
Regimen
Study | Evidence |
Ekeblad et al. 2007 | Phase II |
Chemotherapy
- Temozolomide (Temodar) as follows:
- Cycle 1: 100 or 150 mg/m2 PO once per day on days 1 to 5
- Cycle 2 onwards: increased as tolerated up to 200 mg/m2 PO once per day on days 1 to 5
Supportive medications
- Tropisetron (Navoban) (dose/route/schedule not specified) routinely used as an antiemetic
28-day cycles, given until progression of disease or unacceptable toxicity
References
- Ekeblad S, Sundin A, Janson ET, Welin S, Granberg D, Kindmark H, Dunder K, Kozlovacki G, Orlefors H, Sigurd M, Oberg K, Eriksson B, Skogseid B. Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors. Clin Cancer Res. 2007 May 15;13(10):2986-91. link to original article contains verified protocol PubMed
Neuroendocrine tumors of unknown primary, poorly differentiated (high-grade) neuroendocrine tumors
The NCCN Guidelines, Neuroendocrine tumors version 1.2013, suggests that these are treated with a small cell lung cancer regimen.
Pancreatic neuroendocrine islet cell tumors
Everolimus (Afinitor)
back to top |
Regimen
Study | Evidence | Comparator | Efficacy |
Yao et al. 2010 | Phase II | ||
Yao et al. 2011 (RADIANT-3) | Phase III | Placebo | Superior PFS |
Chemotherapy
- Everolimus (Afinitor) 10 mg PO once per day
Given until progression of disease, unacceptable toxicity, drug interruption of 3 weeks or longer, or withdrawal of consent
References
- Yao JC, Lombard-Bohas C, Baudin E, Kvols LK, Rougier P, Ruszniewski P, Hoosen S, St Peter J, Haas T, Lebwohl D, Van Cutsem E, Kulke MH, Hobday TJ, O'Dorisio TM, Shah MH, Cadiot G, Luppi G, Posey JA, Wiedenmann B. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol. 2010 Jan 1;28(1):69-76. Epub 2009 Nov 23. link to original article contains verified protocol PubMed
- Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, Hobday TJ, Okusaka T, Capdevila J, de Vries EG, Tomassetti P, Pavel ME, Hoosen S, Haas T, Lincy J, Lebwohl D, Öberg K; RAD001 in Advanced Neuroendocrine Tumors, Third Trial (RADIANT-3) Study Group. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011 Feb 10;364(6):514-23. link to original article contains verified protocol PubMed
- Review: Yao JC, Phan AT, Jehl V, Shah G, Meric-Bernstam F. Everolimus in advanced pancreatic neuroendocrine tumors: the clinical experience. Cancer Res. 2013 Mar 1;73(5):1449-53. Epub 2013 Feb 22. link to original article PubMed
Lanreotide (Somatuline) Depot/Autogel
back to top |
Regimen
Study | Evidence | Comparator | Efficacy |
Caplin et al. 2014 (CLARINET) | Phase III | Placebo | Superior PFS |
Endocrine therapy
- Lanreotide (Somatuline) Depot/Autogel 120 mg deep subcutaneous injection once on day 1
4-week cycle for 96 weeks (CLARINET), until progression of disease, or unacceptable toxicity
Patients in NET729 (unpublished) could be treated for up to 8 years.
References
- Caplin ME, Pavel M, Cwikla JB, Phan AT, Raderer M, Sedlácková E, Cadiot G, Wolin EM, Capdevila J, Wall L, Rindi G, Langley A, Martinez S, Blumberg J, Ruszniewski P; CLARINET Investigators. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014 Jul 17;371(3):224-33. link to original article contains verified protocol PubMed
- Lanreotide (Somatuline) package insert
- NIHR (National Institute for Health Research) Horizon Scanning Centre, School of Health & Population Sciences, University of Birmingham. Lanreotide for unresectable, locally advanced or metastatic gastroenteropancreatic neuroendocrine tumours – first line
- ClinicalTrials.gov: Study of Lanreotide Autogel 120mg in Patients With Non-functioning Entero- Pancreatic Endocrine Tumour (NET729)
Lanreotide & Interferon alfa
back to top |
Regimen
Study | Evidence |
Fjällskog et al. 2002 | Pilot, <20 pts |
Fjällskog et al. 2002 contained case reports of several patients treated with lanreotide & interferon alfa. Each patient received individualized therapy rather than a standard regimen.
Endocrine & Immunotherapy
- Lanreotide (Somatuline) 3 mg SC BID
- Interferon alfa-2b (Intron-A) 3 to 5 million units SC given once per day, 3 to 7 days per week (total of 9 to 25 million units per week)
References
- Fjällskog ML, Sundin A, Westlin JE, Oberg K, Janson ET, Eriksson B. Treatment of malignant endocrine pancreatic tumors with a combination of alpha-interferon and somatostatin analogs. Med Oncol. 2002;19(1):35-42. link to original article PubMed
Octreotide (Sandostatin)
back to top |
Regimen
Study | Evidence |
Oberg et al. 2004 | Consensus guideline |
Endocrine therapy
- Octreotide (Sandostatin) 0.1 to 0.5 mg SC given 2 to 4 times per day, with dose increased by doubling the dose every 3 to 4 days as needed to control symptoms
- "A reasonable starting dose is" Octreotide (Sandostatin) 0.15 mg SC TID
Treatment continued indefinitely unless patients have unmanageable side-effects or insufficient control of symptoms
References
- Brentjens R, Saltz L. Islet cell tumors of the pancreas: the medical oncologist's perspective. Surg Clin North Am. 2001 Jun;81(3):527-42. link to original article PubMed
- Review: Oberg K, Kvols L, Caplin M, Delle Fave G, de Herder W, Rindi G, Ruszniewski P, Woltering EA, Wiedenmann B. Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system. Ann Oncol. 2004 Jun;15(6):966-73. link to original article contains verified protocol PubMed
Octreotide LAR (Sandostatin LAR)
back to top |
Regimen #1
Study | Evidence |
Oberg et al. 2004 | Consensus guideline |
Endocrine therapy
- Octreotide LAR (Sandostatin LAR) 20 to 30 mg IM once on day 1, with potentially higher doses if needed for symptom control
- "As a general rule, if the total [octreotide] IR dose is 200–600 µg/day, LAR 20 mg should be tried, and if total IR dose is 750–1500 µg/day, LAR 30 mg should be tried."
- Octreotide (Sandostatin) (dose not specified) SC as needed for additional symptom control
28-day cycles; treatment continued indefinitely unless patients have unmanageable side-effects or insufficient control of symptoms
Regimen #2
Study | Evidence | Comparator | Efficacy |
Rinke et al. 2009 (PROMID) | Phase III | Placebo | Superior TTP |
Endocrine therapy
- Octreotide LAR (Sandostatin LAR) 30 mg IM once on day 1, with potentially higher doses if needed for symptom control
28-day cycles, given until progression of disease
References
- Review: Oberg K, Kvols L, Caplin M, Delle Fave G, de Herder W, Rindi G, Ruszniewski P, Woltering EA, Wiedenmann B. Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system. Ann Oncol. 2004 Jun;15(6):966-73. link to original article contains verified protocol PubMed
- Rinke A, Müller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, Mayer C, Aminossadati B, Pape UF, Bläker M, Harder J, Arnold C, Gress T, Arnold R; PROMID Study Group. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 2009 Oct 1;27(28):4656-63. Epub 2009 Aug 24. link to original article contains verified protocol PubMed
Octreotide & Everolimus
back to top |
Regimen #1
Study | Evidence |
Yao et al. 2010 | Phase II |
Patients in Yao et al. 2010 who received this regimen had already been receiving octreotide LAR for at least 3 months before participating in the study.
Endocrine & Chemotherapy
- Octreotide LAR (Sandostatin LAR) ≤30 mg (whatever their prestudy dose was) IM once every 28 days
- Everolimus (Afinitor) 10 mg PO once per day
Given until progression of disease, unacceptable toxicity, drug interruption of 3 weeks or longer, or withdrawal of consent
Regimen #2
Study | Evidence |
Yao et al. 2008 | Phase II |
Note: Everolimus "dose of 10 mg was associated with superior PFS...however, the study was not prospectively powered for these comparisons. These analyses should be considered exploratory."
Endocrine & Chemotherapy
- Octreotide LAR (Sandostatin LAR) 30 mg IM once on day 1
- Everolimus (Afinitor) 5 or 10 mg PO once per day on days 1 to 28
28-day cycle for up to 12 cycles or until progression of disease, though treatment could be continued beyond this period if thought by the treating physician to be beneficial
References
- Yao JC, Phan AT, Chang DZ, Wolff RA, Hess K, Gupta S, Jacobs C, Mares JE, Landgraf AN, Rashid A, Meric-Bernstam F. 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 Sep 10;26(26):4311-8. link to original article contains verified protocol PubMed
- Yao JC, Lombard-Bohas C, Baudin E, Kvols LK, Rougier P, Ruszniewski P, Hoosen S, St Peter J, Haas T, Lebwohl D, Van Cutsem E, Kulke MH, Hobday TJ, O'Dorisio TM, Shah MH, Cadiot G, Luppi G, Posey JA, Wiedenmann B. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol. 2010 Jan 1;28(1):69-76. Epub 2009 Nov 23. link to original article contains verified protocol PubMed
Octreotide & Interferon alfa
back to top |
Regimen
Study | Evidence |
Fjällskog et al. 2002 | Pilot, <20 pts |
Fjällskog et al. 2002 contained case reports of several patients treated with octreotide & interferon alfa. Each patient received individualized therapy rather than a standard regimen.
Endocrine & Immunotherapy
- Octreotide (Sandostatin) 0.05 to 0.5 mg SC given 2 to 3 times per day
- Interferon alfa-2b (Intron-A) 3 to 5 million units SC given once per day, 3 to 7 days per week (total of 9 to 25 million units per week)
References
- Janson ET, Oberg K. Long-term management of the carcinoid syndrome. Treatment with octreotide alone and in combination with alpha-interferon. Acta Oncol. 1993;32(2):225-9. link to original article PubMed
- Fjällskog ML, Sundin A, Westlin JE, Oberg K, Janson ET, Eriksson B. Treatment of malignant endocrine pancreatic tumors with a combination of alpha-interferon and somatostatin analogs. Med Oncol. 2002;19(1):35-42. link to original article PubMed
- Fazio N, de Braud F, Delle Fave G, Oberg K. Interferon-alpha and somatostatin analog in patients with gastroenteropancreatic neuroendocrine carcinoma: single agent or combination? Ann Oncol. 2007 Jan;18(1):13-9. Epub 2006 Jun 23. link to original article PubMed
Placebo
back to top |
Regimen
Study | Evidence | Comparator | Efficacy |
Rinke et al. 2009 (PROMID) | Phase III | Octreotide LAR | Inferior TTP |
Raymond et al. 2011 | Phase III | Sunitinib | Seems to have inferior OS |
Yao et al. 2011 (RADIANT-3) | Phase III | Everolimus | Inferior PFS |
Caplin et al. 2014 (CLARINET) | Phase III | Lanreotide | Inferior PFS |
No active antineoplastic treatment. Used as a comparator arm and here for reference purposes only.
References
- Rinke A, Müller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, Mayer C, Aminossadati B, Pape UF, Bläker M, Harder J, Arnold C, Gress T, Arnold R; PROMID Study Group. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 2009 Oct 1;27(28):4656-63. Epub 2009 Aug 24. link to original article contains verified protocol PubMed
- Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, Valle J, Metrakos P, Smith D, Vinik A, Chen JS, Hörsch D, Hammel P, Wiedenmann B, Van Cutsem E, Patyna S, Lu DR, Blanckmeister C, Chao R, Ruszniewski P. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011 Feb 10;364(6):501-13. link to original article contains verified protocol PubMed
- Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, Hobday TJ, Okusaka T, Capdevila J, de Vries EG, Tomassetti P, Pavel ME, Hoosen S, Haas T, Lincy J, Lebwohl D, Öberg K; RAD001 in Advanced Neuroendocrine Tumors, Third Trial (RADIANT-3) Study Group. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011 Feb 10;364(6):514-23. link to original article contains verified protocol PubMed
- Caplin ME, Pavel M, Cwikla JB, Phan AT, Raderer M, Sedlácková E, Cadiot G, Wolin EM, Capdevila J, Wall L, Rindi G, Langley A, Martinez S, Blumberg J, Ruszniewski P; CLARINET Investigators. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014 Jul 17;371(3):224-33. link to original article contains verified protocol PubMed
Streptozocin & Doxorubicin
back to top |
Regimen
Study | Evidence | Comparator | Efficacy |
Moertel et al. 1992 | Phase III | Chlorozotocin | Superior OS |
Streptozocin & Fluorouracil | Superior OS |
Chemotherapy
- Streptozocin (Zanosar) 500 mg/m2 IV once per day on days 1 to 5
- Doxorubicin (Adriamycin) 50 mg/m2 IV once per day on days 1 & 22
6-week cycles, given until progression of disease
References
- Moertel CG, Lefkopoulo M, Lipsitz S, Hahn RG, Klaassen D. Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med. 1992 Feb 20;326(8):519-23. link to original article contains verified protocol PubMed
Streptozocin, Doxorubicin, Fluorouracil (FAS)
back to top |
FAS: Fluorouracil, Adriamycin (Doxorubicin), Streptozocin
Regimen
Study | Evidence |
Kouvaraki et al. 2004 | Retrospective |
Chemotherapy
- Fluorouracil (5-FU) 400 mg/m2 IV bolus once per day on days 1 to 5
- Doxorubicin (Adriamycin) 40 mg/m2 IV bolus once on day 1
- Streptozocin (Zanosar) 400 mg/m2 IV bolus once per day on days 1 to 5
28-day cycles, given until progression of disease, unacceptable toxicity, or patient intolerance
References
- Retrospective: Kouvaraki MA, Ajani JA, Hoff P, Wolff R, Evans DB, Lozano R, Yao JC. Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas. J Clin Oncol. 2004 Dec 1;22(23):4762-71. link to original article contains verified protocol PubMed
Streptozocin & Fluorouracil
back to top |
Regimen
Study | Evidence | Comparator | Efficacy |
Moertel et al. 1992 | Phase III | Chlorozotocin | Seems not superior |
Streptozocin & Doxorubicin | Inferior OS |
Chemotherapy
- Streptozocin (Zanosar) 500 mg/m2 IV once per day on days 1 to 5
- Fluorouracil (5-FU) 400 mg/m2 IV bolus once per day on days 1 to 5
6-week cycles, given until progression of disease
References
- Moertel CG, Lefkopoulo M, Lipsitz S, Hahn RG, Klaassen D. Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med. 1992 Feb 20;326(8):519-23. link to original article contains verified protocol PubMed
Sunitinib (Sutent)
back to top |
Regimen
Study | Evidence | Comparator | Efficacy |
Raymond et al. 2011 | Phase III | Placebo | Seems to have superior OS |
Chemotherapy
- Sunitinib (Sutent) 37.5 mg PO once per day
Given until progression of disease, unacceptable toxicity, or patient death
References
- Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, Valle J, Metrakos P, Smith D, Vinik A, Chen JS, Hörsch D, Hammel P, Wiedenmann B, Van Cutsem E, Patyna S, Lu DR, Blanckmeister C, Chao R, Ruszniewski P. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011 Feb 10;364(6):501-13. link to original article contains verified protocol PubMed
Temozolomide (Temodar)
back to top |
Regimen
Study | Evidence |
Ekeblad et al. 2007 | Phase II |
Chemotherapy
- Temozolomide (Temodar) as follows:
- Cycle 1: 100 or 150 mg/m2 PO once per day on days 1 to 5
- Cycle 2 onwards: increased as tolerated up to 200 mg/m2 PO once per day on days 1 to 5
Supportive medications
- Tropisetron (Navoban) (dose/route/schedule not specified) routinely used as an antiemetic
28-day cycles, given until progression of disease or unacceptable toxicity
References
- Ekeblad S, Sundin A, Janson ET, Welin S, Granberg D, Kindmark H, Dunder K, Kozlovacki G, Orlefors H, Sigurd M, Oberg K, Eriksson B, Skogseid B. Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors. Clin Cancer Res. 2007 May 15;13(10):2986-91. link to original article contains verified protocol PubMed
Temozolomide & Bevacizumab
back to top |
Regimen
Study | Evidence |
Chan et al. 2012 | Phase II |
Chemotherapy
- Temozolomide (Temodar) 150 mg/m2 PO once per day on days 1 to 7, 15 to 21
- Bevacizumab (Avastin) 5 mg/kg IV once per day on days 1 & 15
Supportive medications
- Trimethoprim/Sulfamethoxazole (Bactrim DS) 160/800 mg PO once every Monday, Wednesday, and Friday; allergic patients received alternate Pneumocystis carinii (PCP) prophylaxis
- Acyclovir (Zovirax) 400 mg PO TID as prophylaxis against varicella zoster
28-day cycles, given until progression of disease or unacceptable toxicity
References
- Chan JA, Stuart K, Earle CC, Clark JW, Bhargava P, Miksad R, Blaszkowsky L, Enzinger PC, Meyerhardt JA, Zheng H, Fuchs CS, Kulke MH. Prospective study of bevacizumab plus temozolomide in patients with advanced neuroendocrine tumors. J Clin Oncol. 2012 Aug 20;30(24):2963-8. Epub 2012 Jul 9. link to original article contains verified protocol PubMed
Temozolomide & Capecitabine
back to top |
Regimen
Study | Evidence |
Strosberg et al. 2011 | Retrospective |
Chemotherapy
- Temozolomide (Temodar) 200 mg/m2 PO once per day at bedtime on days 10 to 14
- Capecitabine (Xeloda) 750 mg/m2 PO BID on days 1 to 14
Supportive medications
- Ondansetron (Zofran) 8 mg (route not specified) prior to each dose of Temozolomide (Temodar)
28-day cycles
References
- Retrospective: Strosberg JR, Fine RL, Choi J, Nasir A, Coppola D, Chen DT, Helm J, Kvols L. First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas. Cancer. 2011 Jan 15;117(2):268-75. Epub 2010 Sep 7. link to original article contains verified protocol PubMed
Temozolomide & Thalidomide
back to top |
Regimen
Study | Evidence |
Kulke et al. 2006 | Phase II |
Chemotherapy
- Temozolomide (Temodar) 150 mg/m2 PO once per day on days 1 to 7, 15 to 21
- Thalidomide (Thalomid) 200 mg PO once per day
28-day cycles, given until progression of disease or unacceptable toxicity
References
- Kulke MH, Stuart K, Enzinger PC, Ryan DP, Clark JW, Muzikansky A, Vincitore M, Michelini A, Fuchs CS. Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. J Clin Oncol. 2006 Jan 20;24(3):401-6. link to original article contains verified protocol PubMed
Pheochromocytoma
Cyclophosphamide, Vincristine, Dacarbazine (CVD)
back to top |
CVD: Cyclophosphamide, Vincristine, Dacarbazine
Regimen
Study | Evidence |
Averbuch et al. 1988 | Pilot, <20 pts |
Chemotherapy
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
- Vincristine (Oncovin) 1.4 mg/m2 IV once on day 1
- Dacarbazine (DTIC) 600 mg/m2 IV once per day on days 1 & 2
21-day cycles
References
- Averbuch SD, Steakley CS, Young RC, Gelmann EP, Goldstein DS, Stull R, Keiser HR. Malignant pheochromocytoma: effective treatment with a combination of cyclophosphamide, vincristine, and dacarbazine. Ann Intern Med. 1988 Aug 15;109(4):267-73. link to original article contains protocol PubMed
131I-Metaiodobenzylguanidine (131I-MIBG)
Also known as m-[131I]iodobenzylguanidine ([131I]MIBG).
Regimen #1
Study | Evidence |
Rose et al. 2003 | Pilot, <20 pts |
Patients underwent stem cell harvest prior to treatment in case autologous stem cell infusion was needed.
Radiotherapy
- 131I-Metaiodobenzylguanidine (131I-MIBG) 12 to 18 mCi/kg (maximum single dose of 850 mCi) IV over 2 hours once on day 1
Supportive medications
- Intravenous fluids started 12 hours before 131I-MIBG administration.
- Potassium iodide (KI) 6 mg/kg PO once at least 2 hours prior to 131I-MIBG, then potassium iodide (KI) 0.88 mg/kg PO Q4H x 7 days, then potassium iodide (KI) 1 mg/kg PO (frequency not specified) "for 45 days after the infusion."
- Potassium perchlorate 8 mg/kg once at least 2 hours prior to 131I-MIBG, then potassium perchlorate 2 mg/kg PO Q6H x 5 days.
"Repeat 131I-MIBG treatments were administered on a case-by-case basis in an effort to improve the overall response"
Regimen #2
Study | Evidence |
Krempf et al. 1991 | Pilot, <20 pts |
Radiotherapy
- m-[131I]iodobenzylguanidine ([131I]MIBG) 740 megabequerel/mg every 3 months
References
- Krempf M, Lumbroso J, Mornex R, Brendel AJ, Wemeau JL, Delisle MJ, Aubert B, Carpentier P, Fleury-Goyon MC, Gibold C et al. Use of m-[131I]iodobenzylguanidine in the treatment of malignant pheochromocytoma. J Clin Endocrinol Metab. 1991 Feb;72(2):455-61. link to original article contains protocol PubMed
- Rose B, Matthay KK, Price D, Huberty J, Klencke B, Norton JA, Fitzgerald PA. High-dose 131I-metaiodobenzylguanidine therapy for 12 patients with malignant pheochromocytoma. Cancer. 2003 Jul 15;98(2):239-48. link to original article contains verified protocol PubMed