Selective arterial chemoembolization for hepatic metastases from medullary thyroid carcinoma

Selective arterial chemoembolization for hepatic metastases from medullary thyroid carcinoma Kerstin Lorenz, MD,a Michael Brauckhoff, MD,a Curd Behrmann, MD,b Carsten Sekulla, PhD,a Jo¨rg Ukkat, MD,a Katrin Brauckhoff, MD,a Oliver Gimm, MD,a and Henning Dralle, MD, FRCS,a Halle, Germany

Background. Hepatic metastases from medullary thyroid carcinoma (MTC) may impair quality of life by hypercalcitonemia-associated diarrhea and pain. In this prospective study, the effect of selective arterial chemoembolization (SACE) was evaluated. Methods. Eleven patients with hepatic metastases from MTC received 1 to 9 courses of SACE using epirubicine. Symptomatic, biochemical, and morphologic responses on SACE were recorded. Results. Symptomatic response was observed in all symptomatic patients. However, biochemical and radiologic response occurred only in 6 patients. Liver function was not affected by SACE. One patient with unexpected concurrent pheochromocytoma metastases died after the first course. Development of side effects in the course was observed in 8 patients but were only World Health Organization grade 1. Patients’ satisfaction with SACE was excellent. Long-term follow-up found 7 patients alive (1-72 months). Three patients died with tumor 6, 12, and 24 months after SACE, respectively. Conclusion. SACE provided good symptom palliation for the majority of patients with hepatic metastases from MTC. However, transient remission or stabilization of hepatic metastases resulted in only 60%. Further studies using a randomized protocol are required. (Surgery 2005;138:986-93.) From the Departments of General, Visceral and Vascular Surgerya and the Department of Radiology,b Martin-Luther University of Halle-Wittenberg, Germany

HEPATIC METASTASES from medullary thyroid carcinoma (MTC) typically present as small and multiple nodules (Fig 1).1-4 Systemic spread occurs, in descending frequency, in liver, lungs, and bone.5,6 Calcitonin and carcino-embryoitic antigen (CEA) are sensitive tumor markers for advanced MTC, correlating closely with the tumor volume.7,8 The clinical course of patients with metastases from MTC varies widely and includes patients with aggressive tumors as well as patients with very slow tumor growth and long-term survival of more than 15 to 20 years.9 However, MTC may impair quality of life regarding hypercalcitonemia-associated diarrhea or pain from local tumor growth. Currently, no curative therapeutic options in systemic MTC are available. Preliminary results of palliative systemic chemotherapy regimen, Accepted for publication September 22, 2005. Reprint requests: K. Lorenz, MD, Department of General, Visceral and Vascular Surgery, University of Halle, Klinikum Kro¨llwitz, Ernst-Grube-Str. 40, D-06097 Halle, Germany. E-mail: [email protected]. 0039-6060/$ - see front matter Ó 2005 Mosby, Inc. All rights reserved. doi:10.1016/j.surg.2005.09.020

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irradiation and somatostatin analogue are not convincing.9,10 However, with respect to the variable and unpredictable clinical course and prospect of long-term survival in MTC, palliation of tumorrelated symptoms with high efficacy and low rate of side effects is required. Indications and outcomes for available therapeutic options in this setting are poorly defined. Chemoembolization proved effective in liver metastases of neuroendocrine gastrointestinal tumors (NET); however, no data concerning chemoembolization in liver metastases from MTC are available so far. This prospective evaluation study was undertaken to clarify the effect of selective arterial chemoembolization (SACE) in patients with hepatic metastases from MTC in a clearly palliative setting. PATIENTS AND METHODS Patients. Of 429 patients with MTC treated between January 1997 and December 2004 in our institution, 11 consecutive patients (6 men, 5 women), mean age 53 years (range, 29 to 65), who fulfilled inclusion criteria, underwent SACE in this prospective evaluation study. Histologic proof of hepatic metastases from MTC was gained by biopsy at

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Fig 1. Aspect of hepatic and pulmonary metastases from MTC at diagnostic thoracolaparoscopy. A, Disseminated hepatic metastases from MTC shown by laparoscopy in patient 3. B, Disseminated pulmonary metastases from MTC shown by thoracoscopy in patient 3.

ultrasound, computed tomography (CT) and during thoraco-laparoscopic procedures, respectively. There was a sporadic form of MTC in 2 and hereditary (MEN2A, RET protooncogene mutation, Codon 634) MTC in 2 patients. Primary tumor stages of MTC (UICC 1997) of the thyroid comprised pT1 (n = 1), pT2 (n = 2), pT3 (n = 2), and pT4 (n = 5) and pN0 (n = 1), pN1a (n = 7), and pN1b (n = 1) categories. All patients previously underwent first- or second-line total thyroidectomy and lymph node dissection, more so a variety of additional therapies, and 8 patients were referred for remedial surgery with local and lymphonodal recurrence before SACE (Table I). Indication for SACE included patients with irresectable multiple liver metastases from MTC with progressive growth or associated with calcitonin-related diarrhea refractory to medical treatment or local pain from liver metastases. Exclusion criteria included portal vein thrombosis, liver

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cirrhosis stage C according to CHILD-Pugh classification, and severely impaired hepatic function.11 Extrahepatic distant metastases did not serve as exclusion criteria and were found in 4 patients (bone in 4, pulmonary in 3, and brain in 1). Prerequisite laboratory tests assured sufficient hepatic and renal function in all patients. All patients gave informed consent to treatment and study. Demographic data of the patients are summarized in Table I. Technique of selective arterial chemoembolization. For SACE, a 6-hour fasting period was abided. Medical pretreatment consisted of 7.5 mg piritramid, 8 mg ondansetron, 100 mg prednisolone, and 5,000 international unit of heparin intravenously administered. In addition, benzodiazepines and H1and H2-blockers were given before the procedure as required. Before SACE, preliminary arteriography evaluated vascular supply and anatomic variants of the liver and showed patency of the portal vein. SACE emulsion was prepared individually and consisted of 2 to 10 mL Lipiodol ultra fluid, an iodised oil contrast medium (Guerbet GmbH, Sulzbach, Germany); 5 to10 mg Spherex, consistent of biodegradable starch particles (PharmaCept GmbH, Berlin, Germany); and epirubicine. Composition and applicable dose varied individually and depended on the actual liver uptake. In normal portal anatomy, application of SACE was preferably applied to the total liver by consecutive selective catheterization of right and left hepatic arteries. Only in instances of atypical vascular anatomy or diminished uptake, superselective catheterization for SACE using a microcatheter was performed (Tracker catheter, Target Therapeutics, San Jose, Calif). Under angiographic control, the SACE emulsion was aimed at equal injection into each liver lobe until stasis within the vessels was achieved or reflux observed (Fig 2). Patients experiencing pain during SACE received additional piritramid as required. SACE courses were repeated in monthly intervals until recognizable response was noted. Judged from experience with SACE in other tumor entities, the protocol assigned 6 SACE procedures as full treatment and 9 intended for consolidation of effect. In case diminished hepatic uptake or considerate progressive tumor growth was observed, intervals were prolonged or SACE was discontinued. Treatment protocol and definition of treatment response. The treatment protocol applied here was abutted on our experience with SACE for hepatocellulary carcinoma and reports of SACE in other neuroendocrine tumors, eg, carcinoids.12-15

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Table I. Patient demographics, tumor stages, and previous treatment modalities Patient, gender, age at primary diagnosis, y 1, M, 46 2, M, 54 3, M, 23

Etiology

TNM UICC 1997

Her MEN2A pT3pN1M1 (codon 634) (hep) Spor pT4pN1M2 (hep bone) Spor pT4pN1bLoVoR1

4, M, 61

Spor

pT4pN1M1 (hep) pT4NxM2 (hep pulm)

5, F, 56

Spor

6, F, 53

Spor

pT2pN1Mx

7, F, 61

Spor

pT4pN1aMx

8, F, 37

Her MEN2A pT2bpN0M0 (codon 634)

9, F, 26

Spor

10, M, 56

Spor

11, M, 45

Spor

pT1pN1bM1 (hep) pT4pN1bMx

pT3mpN1M1 (hep)

Surgery before SACE

Palliative treatment Time from modalities PD to before SACE SACE, mo

Tot. thyroidectomy + — 12 K1a + K1b Tot. thyroidectomy + — 117 K1a K1a+K4 K1a+b 59 Tot. thyroidectomy sel. ext RX RIT RIT cervical LA sel. anti-CEA cervical LA diag. thoraco-laparoscopy, biopsy liver + lung Tot. thyroidectomy + — 1 K1-4 — 10 Tot. thyroidectomy diag. thoracolaparoscopy, biopsy liver + lung K1-K3 — 126 Hemithyroidectomy l hemithyroidectomy r K1b Tot. thyroidectomy + — 18 K1b K1-K3 PTX tot. thyroidectomy ext RX RIT 319 sel. cervical LA Sel. cervical LA sel. cervical LA liver B adrenalectomy UL hemihepatectomy R Tot. thyroidectomy + — 52 K1a K1a+K2 K1-K3 — 15 Tot. thyroidectomy K1-K4 res VJI, res. RLN r K2 diagn. laparoscopy liver biopsy S6 LNE cervical tot. — 2 thyroidectomy + K1-3

Remedial surgery during SACE — —

sel. cerv. LA sel. cerv. LA K2 dorsal vertebral stabilisation — right hemihepatectomy, thermoablation left liver sel. cervical LA

K3 —

— —

—

MTC, Medullary thyroid carcinoma; CE, chemoembolization; spor, sporadic; her, hereditary; tot, total; diag, diagnostic; K1a, systematic microdissection of right cervicocentral lymph node compartment; K1b, left cervicocentral; K2, right cervicolateral; K3, left cervicolateral; K4, mediastinal; res, resection; VJI, inferior jugular vein; RLN, recurrent laryngeal nerve; sel, selective; LA, lymphadenectomy; ext RX, external radiation; RIT, radioiodine therapy; anti-CEA, anti-CEA-antibody therapy; cerv, cervical; LNE, selective diagnostic lymphnode exstirpation; PD, primary diagnosis.

Response was defined according to standard World Health Organization (WHO) criteria. A symptomatic response was defined as complete (complete resolution of symptoms), partial (decrease of intensity or frequency of symptoms), or no change (unchanged symptoms). Data were assessed repeatedly by patient questionnaire. Additional information was acquired from hospital charts and the primary physicians. A biochemical response was defined as decrease greater than 10% of the

initial value of tumor markers calcitonin and CEA, partial biochemical response was determined as decrease of less than 10% of calcitonin or CEA and progression as increase of calcitonin and CEA from basal values previous to the first SACE. Finally, a complete radiologic response to SACE was defined when radiologic findings showed complete decrease of hepatic lesions compared with initial CT or magnetic resonance imaging, partial response was determined as greater than 50%

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criteria, development of tumor markers, and alleviation of symptoms that were assessed by records from chart and questionnaire, respectively. Furthermore, assessment by outpatient visits, patients’ questionnaires, telephone interviews, and information from primary physicians and radiologists were included. Statistics. Data were analyzed statistically using Excel calculation program, SPPS 12.0 and the Kaplan-Meier method for survival calculation.

Fig 2. Angiographic image of SACE for hepatic metastases from MTC in patient 1.

reduction of lesions in size or number, minor response appointed less than 50% reduction, stable disease was defined as unchanged number and size of metastases, and progression was an increase of greater than 50% in size or number of hepatic lesions. Variable doses at individual SACE courses were owing to the changeable hepatic uptake. Whenever considerable hepatic vascular spasm or reflux precluded application of a relevant dose, interval of SACE was prolonged or discontinued. Evaluation of response was recorded after 3, 6, and 9 interventions, respectively. Complications, side effects, and toxicity were recorded from hospital charts, assessed by patient’s questionnaire, and rated according to WHO criteria. Four patients received remedial operation during SACE for local or lymphonodal recurrence. In 1 patient, hepatic response to SACE facilitated subsequent hemihepatectomy. None of the patients received other additional tumor-directed treatment modalities during SACE except for symptomatic medication for pain or diarrhea. Symptomatic, biochemical, and radiologic responses served as primary endpoints. All-over survival for patients with hepatic metastases only and patients with additional distant metastases but all-over survival did not serve as endpoint in this evaluation for the palliative intended treatment. Side effects and toxicity encountered during and after SACE were recorded by chart and patient questionnaire. Follow-up. Characteristics of tumor response to treatment were evaluated according to radiologic

RESULTS Synchronous hepatic manifestation of MTC at initial diagnosis was found in 6 patients. There was evidence of further distant metastases to the bone in 4 patients, to the lung in 3, and the brain in 1 patient, respectively. In 5 patients with metachronous evidence of hepatic metastases, mean interval from primary diagnosis of MTC to proven hepatic manifestation was 81 months (range, 1 to 216 months). Mean latency from primary diagnosis to first SACE for all patients was 73 months (range, 1 to 317 months). Total number of SACE procedures varied from 1 to 9 (Table II). Because of one death after the first SACE, all results and follow-up refer to the remaining 10 patients. Mean follow-up from first SACE to last contact was 35 months (range, 15 to 72 months). Specific symptoms were observed in 8 patients and comprised diarrhea in 6 patients (range, 3 to 11 stool frequency per day/night during 5 to 7 d/wk) and liver or upper abdominal pain in 4 patients. There were general symptoms with loss of efficiency in 7, fatigue in 5, depression in 2, and involuntary weight loss in 3 patients, respectively. Overall symptomatic response was observed in 88% (7 of 8) of patients. Symptomatic response within the first 3 courses occurred in all responders. Further improvement of life quality parameters occurred in 7 patients. However, continuous improvement of life quality parameters until the last SACE was found in only 2 patients. No further improvement of symptoms was observed in 5 patients after the sixth course. Symptoms of diarrhea and pain were equally present in patients with higher and lower levels of calcitonin or smaller tumor burden. The mean tumor marker levels before SACE were 43,326 pg/mL (range, 581 to 213,421 pg/ mL; normal, <10 pg/mL]) for calcitonin and 129 ng/mL (range, 18 to 237 ng/mL; [normal, <4.5 ng/mL]) for CEA (Table II). Biochemical response occurred in 5 of 10 patients. In comparison from the first to the last SACE, ranging from 6 to12 months according to the total number and timing

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Table II. Response to SACE regarding radiology, biochemistry, symptoms, and survival Tumor markers before SACE

Radiologic Survival response (in from parenthesis) Epirubicine Calcitonin last (max. effect Number of application Calcitonin pg/mL CEA ng/mL after SACE Symptom. SACE pg/mL CEA ng/mL total dose Met. SACE [<10 pg/mL] [<4.5 ng/mL] [<10 pg/mL] [<4.5 ng/mL] course no.) response (mo) (mg) Patient site courses 1 2 3 4 5 6 7 8 9 10 11

L+ L+ L+ L L L L+ L L L+ L

1 5 5 6 6 6 8 8 9 9 9

100 500 470 600 580 515 690 690 640 575 665

2,960 13,410 213,421 896 1,037 3,617 581 187,100 37,667 9,749 6,147

224 116 219 18 237 31 24 167 215 113 151

Tumor markers after SACE

— 3,1520 209,267 68 1,055 733 311 24,696 25,750 9,945 6,601

— 114 214 3 108 21 134 220 179 316 110

— SD (3) SD (5) PR (6) MR (6) MR (6) SD (6) PD (5) PR (7) SD (4) PR (6)

— PR PR R NS R PR PR R PR NS

— LWT 36 LWT 38 LWT 39 LWT 25 LWT 18 DWT 6 DWT 24 LWT 72 DWT 12 LWT 1

R, Complete response; PR, partial response; NS, not symptomatic; LWT, alive with tumor; DWT, died with tumor; L, exclusively liver metastases; L+, additional distant metastases.

of SACE in the individual patient, there was a decrease of calcitonin levels of greater than 10% observed in 5 patients, a decrease less than 10% in 1, and increase in 4 patients (>10%, n = 1; <10%, n = 3). Similarly, CEA levels decreased more than 10% in 5 and less than 10% in 2, and increased in 3 patients. Decrease of tumor markers from the respective pretreatment levels at the individual SACE courses was inconsistent in all patients irrespective of response category, and could be observed until the ninth course of SACE in 3 patients. Differentiation of patients with hepatic metastases only and additional distant metastases showed no significant difference in calcitonin response of a decrease greater than 10% from the first to the last SACE performed (4 of 6 vs 2 of 4) and a decrease of CEA of greater than 10% (4 of 6 vs 3 of 4) within 6 to 12 months of treatment. No patient showed complete radiologic remission. Partial remission occurred in 3, minor remission in 2, stable disease in 4, and progression of hepatic disease in 1, respectively. Subdivision according to evaluation after 3, 6, and 9 courses resulted in partial radiologic response in 2 of 10 patients after 3 SACE courses and in 5 of 8 patients after 6 courses. No further response was achieved in 3 patients with 9 courses (Table III). The variation of hepatic uptake encountered was rendered responsible for the variable dose of chemoembolization emulsion applied in the respective interventions and was found in the majority of patients. Because of the variable hepatic uptake or considerable reflux, total dose of epirubicine applied in the individual patients ranged from 470 mg to 690 mg,

the dose applied with a single SACE ranged from 35 mg to 100 mg. Complication was one procedure-related death owing to catecholamine-related hypertensive crisis with myocardial infarction in a patient with unrecognized concurrent hepatic metastases from pheochromocytoma.16 A 1-cm dissection of the right hepatic artery occurred during catheterization for the fourth SACE in 1 patient, but patency was reconstituted in the course of SACE; another patient showed early local erythema lasting for 1 week on 2 occasions postinterventionally but required no treatment. No chemotherapy-related toxicity (eg, leucopenia) occurred in this series. Pre- and postinterventional assessment of hepatic transamines and blirubin showed only insignificant transient elevation. Side effects were all grade 1 according to WHO, and first onset was observed after 3 courses. Abdominal pain or nausea during the first 24 hours after SACE were registered in 4 of 10 patients after 3 procedures, in 7 of 8 patients after 6, and in all 3 patients after 9 procedures, respectively. Side effects and further symptomatic complaints assessed by patient questionnaire showed slow but steady progression with the number of SACE (Table IV). Long time follow-up showed renewed elevation of tumor markers within a mean of 14 months (range, 4 to 48) and was found in all patients. Oppositely, symptomatic recurrence of mainly diarrhea was noted at a mean of 18 months (range, 10 to 68 months) and was present in 6 of 8, whereas a sustained effect was seen in 4 of 8 patients with 2

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Table III. Effect of SACE on symptoms, biochemistry and radiology with respect to the treatment course After 3 SACE After 6 SACE After 9 SACE courses coursesz courses{ Symptomatic 7*/8y response Biochemical 6*/10y response Radiologic 2*/10y response

6*/6y

2*/3y

6*/8y

2*/3y

5*/8y

0*/3y

*Number of patients with effect achieved. yNumber of patients treated with 3, 6, and 9 courses of SACE, respectively. zResponse from third to the sixth course. {Response from sixth to the ninth course.

remaining asymptomatic from the beginning. Five patients showed progressive liver metastases and additional distant metastases, whereas 2 patients showed stable disease compared with last SACE. Treatment with somatostatin analogue, loperamide, and analgetics concurred with slow radiologic tumor progression and markedly elevated tumor markers in 5 of 7 patients (71%) alive. Seven patients were found alive with tumor at a mean of 30 months from the last SACE (range, 1 to 56 months). Mean survival time in this study was 26 months from the last SACE (range, 1 to 72 months) (Table II). Three patients (30%) died at a mean of 14 months from last SACE (range, 6 to 24 months) (Table II). DISCUSSION The objective of this study was to evaluate results of SACE regarding palliation of symptoms and tumor growth in patients with hepatic metastases from MTC. Patients with minor and advanced primary MTC, pT1 through pT4, equally presented with hepatic metastases, a phenomenon previously emphasized16-21; however, no difference in response according to the pT categories was observed. Response was less than expected with 73% symptomatic response, 50% biochemical, and 60% radiological response. Moreover, the effect was transient, and long-term follow-up showed symptoms of diarrhea, pain, and loss of efficiency in 43% more than 12 months after SACE. Tumor response was first recognized after 3 SACE interventions and after 6 courses. No auxiliary benefit with more than 6 procedures was seen. Therefore, a consolidation of tumor response with continuation beyond 6 courses cannot be shown within this study’s duration and remains unclear. Side effects encountered were only mild.

Table IV. Patient evaluation of effect versus side effects of SACE* Symptom

Side effects

Patient no.

Diarrhea

Unspecific tumor syndromey

Pain

Nausea

1 2 3 4 5 6 7 8 9 10 11

— HS HS MS — HS HS HS HS US —

— US US US MS US MS HS HS MS MS

— HS MS US MS HS MS MS MS MS MS

— HS US MS MS HS HS HS HS HS HS

HS, Highly satisfied; MS, medium satisfied; US, unsatisfied. *As assessed by patient questionnaire after the last SACE. yUnspecific tumor syndrome comprises fatigue, pain, efficiency, and weight loss.

Contrary to expectation, response did not differ significantly between patients with hepatic metastases only and patients with additional distant metastases (Table V). However, survival from the last SACE was better in patients with hepatic disease only (23 vs 30 months). A dominant role of hepatic tumor referring to symptoms in systemic MTC is therefore implied. On the other hand, unrecognized distant metastases may also account for the small biochemical effect found. Feasibility and effect of arterial chemoembolization was seen previously in carcinoids and hepatocellulary carcinoma.13-16 Especially compared with chemoembolization of carcinoid tumors, side effects of SACE in MTC were strikingly mild; hepatic transamines were only insignificantly and transiently elevated, and, without exception, hepatic parameters were always normalized within 4 weeks after SACE. Moreover, fever and considerate malady (embolization syndrome) as infrequently in carcinoids was not encountered. However, pain during and early after SACE was experienced in increasing intensity in all patients beginning at the third procedure. This was not reflected by the patient’s excellent overall satisfaction with the treatment. All except one would again undergo SACE when necessary. This difference between carcinoids and MTC is explained by the lack of biogene amines involved. Also, the predominant micrometases of MTC consecutively amount to less necrosis. This lack of intervention-associated morbidity allowed for selective consecutive chemoembolization of both liver lobes during one SACE procedure whenever hepatic uptake was sufficient.

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Table V. Comparison of response and follow-up between patients with exclusive hepatic and additional distant metastases from MTC

Response Symptomatic

Biochemical Radiologic

Death* Survival*

Liver metastases only (n = 6 of 10) R=3 PR = 1 NS = 2 R=1 PR = 5 MR = 2 PR = 3 P=1 1 (24) M = 30 (1 to 72)

Liver plus additional distant metastases (n = 5 of 10) PR = 4

PR = 2 P=2 SD = 4

2 (6; 12) M = 23 (6 to 38)

R, Complete response; M, mean; MR, minor response; PR, partial response; P, progression; NS, not symptomatic; SD, stable disease. *In months from last SACE.

There was one previously reported lethal complication observed in an MEN2A patient with concomitant hepatic metastases from MTC and underlying, undetected contralateral pheochromocytoma after previous unilateral andrenalectomy.16 It is therefore of paramount importance to exclude metastases and pheochromocytoma before SACE, especially in hereditary form of MTC. Possibly, response might have fulfilled expectations better with a protocol using a more potent chemotherapeutic substance and an extended time schedule with, eg, 8 weeks in between courses of SACE to enhance hepatic uptake. In this study, patients were selected for treatment when symptomatic complaints or rapidly progressive hepatic tumors were present. A potentially better effect may be achieved with earlier implementation of SACE, precluding a larger tumor load. Individual liver uptake at SACE varied; however, the total applicable dose of eprirubicine did not differ significantly. Variation of lipiodol and Spherex at SACE showed no significant influence with respect to response. There was no consideration to divert patients into groups for treatment with embolization only and chemoembolization. It remains therefore open whether response to SACE is accredited more to the antracycline or rather to the hepatic arterial embolization. Economic considerations become increasingly important. Costs for 6 SACE procedures amounted to 9264. V in hospital setting. In case of an ambulatory setting, costs were calculated to be reduced to 7164. V. Therefore, overall treatment costs do not exceed costs of systemic chemotherapies.

Our data established the following clinical protocol and algorithm for palliative treatment of MTC patients with systemic disease in MTC: confirmation of hepatic metastases should be acquired with liver angiography or laparoscopy. According to the type and extension of hepatic metastases, distribution to 1 of 4 treatment arms follows. Patients with resectable metastases and exclusion of disseminated micrometastasis are eligible for hepatic resection. In case of additional few and small lesions in the other lobe, regional ablative measures like radio frequency, laser, or cryoablation may be combined with surgery. Patients with disseminated bilobar hepatic metastases, larger liver lesions with disseminated micrometastases, or dominant and symptomatic hepatic metastases with or without further distant metastases, are candidates for SACE or transarterial chemoembolization (TACE). In case of symptomatic high simultaneous tumor volume of liver, lung, and bone or when response of surgery or SACE fails, regimen of systemic chemotherapy, MIBG-therapy, or radioligands should be considered. In the future, SACE, or even systemic treatment, might be improved with innovative substances like imatinib, gemcitabine, or selective radioligand therapy.21,22 Palliation in the absence of therapeutic alternatives was the primary objective for this subset of patients, and overall response showed benefit in about 50%. This lags behind warranted expectations and therefore protocols in a randomized design are necessary. REFERENCES 1. Van Beers B, Pringot J. Hepatic metastases in medullary thyroid carcinoma: possible pitfall with MR imaging. Eur J Radiol 1990;11:107-9. 2. Tung WS, Vesely TM, Moley JF. Laparoscopic detection of hepatic metastases in patients with residual or recurrent medullary thyroid cancer. Surgery 1995;118:1024-30. 3. Esik O, Szavcsur P, Szakall S, Bajzik G, Repa I, Dabasi G, et al. Angiography effectively supports the diagnosis of hepatic metastases in medullary thyroid carcinoma. Cancer 2001;91:2084-95. 4. Szavcsur P, Go¨deny M, Bajzik G, Lengyel E, Repa I, Tron L, et al. Angiography-proven liver metastases explain low efficacy of lymph node dissections in medullary thyroid cancer patients. Eur J Surg Oncol 2005;31:183-90. 5. Machens A, Ukkat J, Brauckhoff M, Gimm O, Dralle H. Advances in the management of hereditary medullary thyroid cancer. J Int Med 2005;257:50-9. 6. Miraille E, Vuillez JP, Bardet S, Frampas E, Dupas B, Ferrer L, et al. High frequency of bone/bone marrow involvement in advanced medullary thyroid cancer. JC Endocrinol Metab 2005;90:779-88. 7. Machens A, Schneyer U, Holzhausen HH, Dralle H. Prospects of remission in MTC according to basal calcitonin level. J Clin Metabol 2005;90:1-6. 8. Brauckhoff M, Gimm O, Brauckhoff K, Ukkat J, Thomusch O, Dralle H. Calcitonin kinetics in the early postoperative

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DISCUSSION Dr Clive Grant (Rochester, Minnesota). We have had experience using this type of treatment in carcinoid patients, and I am a little surprised that you didn’t have

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higher elevations of liver enzymes and perhaps fever. In our experience, these patients often have significant increase in liver function tests and associated fever even after embolization of a single lobe of the liver. Along the same line, we would expect marked improvement in hormone-related symptoms after just 1 or 2 embolizations, whereas your patients see little improvement until the third or even sixth episode of your SACE. How do you account for (1) the lesser toxicity to their liver and (2) why does it take 3 to 6 treatments? Have you been able to differentiate the effect of the chemotherapy versus just the embolization? We found that devascularization seems to be the important factor. Dr Kerstin Lorenz. Regarding your first question, these are totally different tumor entities. Carcinoids obviously react differently; possibly the necrosis that is reached with SACE and the absence of biogenic amines is different in carcinoid tumors compared with MTC. We did not differentiate embolization and chemoembolization. All patients were treated with epirubicin, although hepatic uptake obviously was variable in these patients. This may be another reason for the different response. Response might possibly be enhanced with different or new chemotherapeutics, which may be more efficient in MTC. Dr Douglas B. Evans (Houston, Texas). How did you pick the 11 patients who were rapidly progressive? What was your definition? Why didn’t you apply chemoembolization or just embolization to patients with less rapidly progressive disease? Maybe you could explain what you define as rapidly progressive disease, and how you would treat the patient who is more common; one who has slow progression of liver metastasis over months to years with a much less rapid increase in calcitonin. Dr Kerstin Lorenz. MTC is rather indolent even in the presence of hepatic metastases. These 11 patients just stood out as being symptomatic with diarrhea, and conservative treatment was not effective. This is why we tried a new treatment option and chose to try SACE. There are obviously 2wo different types of hepatic metastases in these patients. There are patients with a dominant hepatic disease and patients with distant metastases, and these patients may be asymptomatic. It remains unclear whether we reach these micrometastases with SACE. We found some variable responses in our patients. Dr Douglas B. Evans. Are you using chemoembolization now in patients who are asymptomatic but have slowly progressive liver disease? Dr Kerstin Lorenz. No, not all patients had diarrhea or abdominal pain. Of these 11 patients, there were 8 patients who were symptomatic and 2 patients who were not subjectively symptomatic but showed rapidly progressive hepatic disease.