Neuroendocrine Tumors 193
36. Neuroendocrine Tumors
36.1. General considerations
Neuroendocrine tumors are uncommon and optimum management of patients should be by a multidisciplinary approach in centers of expertise!
Literature: for review
BRENTJENS and SALTZ, Surg. Clin. North Am. 81 (2001): 527-542 (islet cell tumors of the pancreas )
CHATAL et al, world J. surg. 24 (2000): 1285-1289 (nuclear medicine applications for neuroendocrine tumors)
COIT, Ann. Surg. Oncol. 8 (Suppl 9) (2001); 99 – 102 (Merkel cell
carcinoma)
De HERDER and LAMBERTS, Curr, Opin. Oncol. 14 (2002); 53-57 (somatostatin and analogs: diagnostic and therapeutic uses)
GOESSLING et al, J. Clin. Oncol. 20 (2002): 588-598
KOPE et al, J. Cancer Res. Clin. Oncol. 127 (2001): 143-155 (magngement of malignant adrenal tumors)
KULKE and MAYER, N. Engl. J. Med. 340 (1999): 858-868 (carcinoid tumors)
MEDINA-FRANCO et al, Ann. Surg. Oncol. 8 (2001): 204-208 (Merkel cell carcinoma)
MITRY and ROUGIER, Crit. Rev. Oncol. Hematol. 37 (2001): 45-51 (treatment of undifferentiated neuroendocrine tumors)
ÖBERG, Curr. Opin. Oncol. 14 (2002):38-45 (carcinoid tumors); Digestion 62 (Suppl 1) (2000): 92-97 (interferon in the treatment of neuroendocrine intestinal tumors)
ORLANDI et al, Endocr. Relat. Cancer 8 (2001): 135-147 (treatment of medullary thyroid carcinoma)
ROUGIER and MITRY , Digestion 62 (Suppl) (2000): 73-78 (chemotherapy in the treatment of neuroendocrine malignant tumors)
SCARPIGNATO and PELOSINI, Chemotherapy 47 (Suppl 2) (2001): 1-29 (somatostatin analogs)
SCHUSSHEIM et al, Trends Endocrinol. Metab. 12(2001): 173-178 (multiple endocrine neoplasia type 1)
WALTHER et al, World. J. Urol. 17 (1999): 35-39 (pheochromocytoma)
WEBSTER, Baillieres Best Pract. Res. Clin. Endocrinol. Metab. 13 (1999): 395-408 (Prolactinomas)
36.2 Carcinoid tumor
36.2.1 Monotherapy
Treatment may be attempted with a somatostatin analog , interferon alpha ,
5- fluorouracil, or doxorubicin, e.g.
36.2.1.1 Octreotide and octreotide long-acting release (LAR) formulation
|
Octreotide 100-200µg s.c. 2-3 times daily |
At least 6 weeks and as long as a response is achieved. Dose escalation to x 2 500
and 2 x 1000 µg is possible in case of insufficient response.
|
Octreotide LAR 20mg i.m. every 4 wks until progression* |
* Supplemental octreotide is needed for approximately 2 weeks after initiation of
octreotide LAR as well as for occasional rescue injections.
194 Neuroendocrine Tumors
Literature:
APARICIO et al, Eur. J. Cancer 37 (2001) : 1014 –1019 (antitumor
activity of octreotide and lanreotide in progressive metastatic
neurendocrine tumors)
ERIKSSON and ÖBERG, Ann. Oncol. 10 (Suppl2) (1999): 31-38 (review
of 15 years of somatostatin analogs)
RICCI et al, Ann. Oncol. 11 (2000):1127-1130 (octreotide LAR in patients
with metastatic neuroendocrine tumors pretreated with lanreotide)
RUBIN et al, J. Clin. Oncol. 17 (1999): 600-606 (octreotide LAR vs
s.c.octreotide in maliganat carcinoid syndrome)
36.2.1.2 Lanreotide
|
Lanreotide 30mg /kg i.v. every 2 wks until progression |
Literature:
APARICIO et al, Eur. J. Cancer 37 (2001): 1014-1019 (antitumor activity
of octreotide and lanreotide in progressive metastatic neurendocrine tumors)
RICCI et al, Am. J. Clin. Oncol. Cancer Clin. Trials 23 (2000): 412-415
WYMENGA et al, J. Clin. Oncol. 17 (1999): 1111-1117
36.2.1.3 Interferon alph
|
Interferon alpha 5x106 IU s.c. d 1, 3, 5 |
To be repeated weekly (at least 6 times; in case of a response until progression)
Literature:
DIRIX et al, Anticancer Drugs 7 (1996); 175- 181
ÖBERG, Digestion 57 (Suppl 1) (1996): 81-83
36.2.1.4 Doxorubicin
|
Doxorubicin 60mg/m2 i.v. (bolus) d 1 |
To be repeated every 3-4 weeks
Literature:
ENGSTROM and LAVIN. J. Clin. Oncol. 2 (1984): 1255-1259 (streptozotocin + 5- fluorouracil vs doxorubicin)
36.2.1.5 5- fluorouracil
|
5-Fluorouracil 500mg /m2 i.v.(bolus) d 1-5 |
To be repeated every 5 weeks
Literature:
MOERTEL, J. Clin. Oncol. 1 (1984): 727-740
36.2.2. Combination chemotherapy
No clear advantage compared to montherapy. e.g.
36.2.2.1 5-Fluorouracil + streptozotocin
|
5-Fluorouracil 400mg/m2 i.v.(bolus) d 1-5 |
|
Streoptozotocin 500 mg/m2 i.v.( short inf) d 1-5 |
To be repeated every 6 weeks
Literature:
MOERTEL and HANLEY, Cancer Clin. Trials 2 (1979): 327-334
Neurooendocrine Tumors 195
36.2.2.2 Etoposide + cisplatin
|
Etoposide 130mg/m2 i.v.(24 h inf) d 1-3 |
|
Cisplatin 45 mg/m2 i.v.( 24 h inf) d 2-3 |
To be repeated every 4 weeks (max 6 cycles)
Literature:
MOERTEL et al, Cancer 68 (1991): 227 – 232
36.3 Islet cell cancer of the pancreas
Treatment may be attempted with somatostatin analogs, or interferon alpha, or streptozotocin, or doxorubicin, or combinations of streptozotocin with 5-fluorouracil or with doxorubicin, or etoposide + cisplatin (see 35.2).
Literature:
ERIKSSON et al, Cancer 65 (1990): 1883-1890
KVOLS and BUCK, Semin, Oncol. 14 (1987): 343-353
MOERTEL, J. Clin. Oncol. 5 (1987): 1503-1522
ÖBERG, Ann. Oncol. 7 (1996): 453-463
36.4 Medullary carcinoma of the thyroid
36.4.1 Monotherapy
Treatment may be attempted with octreotide, or interferon alpha, or doxorubicin (see 36.2).
Literature:
GOTTLIEB and HILL, N. Engl. J. Med. 290 (1974): 193-197
(doxorubicin)
36.4.2 Combination chemotherapy
E.g. CVD
|
Cyclophosphamide 750 mg/m2 i.v. (bolus) d 1 |
|
Vincristine 1.4 mg/m2 i.v.( bolus) d 1 |
|
Dacarbazine 600 mg/m2 i.v. (bolus) d 1+ 2 |
To be repeated every 3-4 weeks (4-6 cycles)
Literature:
WU et sl, Cancer 73 (1994): 432-436
36.5. Adrenal cortical carcinoma
36.5.1 Mitotane (o, p ‘ DDD, Lysodren )
|
Mitotane up to 10 g/d p.o. in 3 divided doses for to months |
Pharmacokinetic monitoring of serum concentrations might be of value with target concentrations > 14 µg/ml being associated with a greater chance of reponse. To offset adrenal insufficiency induced by mitotane, hydrocortisone (30 – 60 mg/d) and fludrocortisone (50mg/d) are administered orally, starting after the second week of mitotane treatment.
Literature:
BOVEN et al, Cancer 53 (1984): 26-29
Van SLOOTEN et al, Eur. J. Cancer Clin. Oncol. 20 (1984): 47-53
WOOTEN and KING, Cancer 72 (1993): 145-155
196 Neuroendocrine Tumors
36.5.2. Chemotherapy
May be attempted with cisplatin ± etoposide, doxorubicin; also in association with mitotane , e.g.
36.5.2.1 Cisplatin
|
Cisplatin 100mg./m2 i.v.( 2 h inf) d 1 |
To be repeated every 3 weeks
Literature:
DHUN et al, Cancer Treat. Rep. 67 (1983): 513-514
36.5.2.2 Doxorubicin
|
Doxorubicin 60 mg/m2 i.v.( bolus) d 1 |
To be repeated every 3 weeks
Literature:
DECKER and KUEHNER. Am. Surg. 57 (1991): 502-513
36.5.2.3 EAP – M
|
Doxorubicin 20 mg/m2 i.v.( bolus) d 1+8 |
|
Cisplatin 40 mg/m2 i.v.( 1 h inf) d 2+9 |
|
Etoposide 100mg/m2 i.v.(1 h inf) d 5-7 |
To be repeated every 4 weeks (max 6 cycles) plus
|
Mitotane maximum tolerated dose ( up to 4 g/d ), continuously until progression or onset of severe toxicity |
Literature:
BERRUTI et al, Cancer 83 (1998): 2194 –2200
36.5.3 In case of hormone hypersecretion
Palliation (but no inhibition of tumor growth) may be achieved with ketoconazole aminoglutethimide or metyrapone.
36.6 Pheochromocytoma
CVD see 36.4.2
Literature :
AVERBUCH et al, Ann. Intern. Med. 109 (1988): 267 – 273
36.7 prolactinomas
Treatment with dopamin agonists (cabergoline, quinagolide are better tolerated and more effective than bromocriptine ). Withdrawal or dose reduction should be considered after 2-5 years of therapy .
Literature:
WEBSTER, Baillieres Best Pract. Res. Clin. Endocrinol. Metab. 13 (1999): 395 – 408 (review)
Neurooendocrine Tumors 197
36.8 Merkel cell tumors
Effective cytostatics are etoposide, cyclophosphamide, cisplatin, methotrexate, doxorubicin, 5-fluorouracil and vinca alkaloids. Treatment can be attempted with combination chemotherapy regimens used for small cell lung cancer.
Literature: e.g.
FENIG et al, Cancer 80 (1997): 881-885
HENSE et al, Tumor Diagn . Ther. 19 (1998): 123-137
PECTASIDES et al, Am. J. Clin. Oncol. (CCT) 18 (1995): 418-420
TAI et al, J. Clin. Oncol. 18 (2000): 2493-2499
36.9 Generally applicable
(Carcinoid, islet cell cancer of the pancreas, medullary carcinoma of the thyroid)
|
5-Fluorouracil 400mg/m2 i.v. d 1-3 |
|
Dacarbazine 200 mg/m2 i.v. (30 min inf) d 1-3 |
|
Etoposide 30mg/m2 i.v. d 1-3 |
To be repeated every 3 weeks (max 9 cycles)
Literature: e.g.
BAJETTA et al, Cancer 83 (1998): 372-378
36.10 Radiopharmaceuticals
Sensitive, specific radiopharmaceuticals are available for diagnosis ([123]I-
Metaiodobenzylguanidine for pheochromocytoma, [111] In- labeled somatostatin
analog octreotide for gastroenteropancreatic and carcinoid tumors), and therapy ([131])I-metaiodobenzylguanidine, [90]Y-octreotide).
Literature: e.g.
CHATAL et al, World J. Surg. 24 (2000): 1285-1289
De JONG et al, Int. J. Cancer 75 (1998): 406 –411
LEIMER et al, J Nucl. Med. 39 (1998): 2090-2094
SMITH- JONES et al, Nucl. Med. Biol. 25 (1998): 181-188