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Department of Nuclear Medicine and Endocrine Tumors (J.F., E.B., S.L., M.S.), Interventional Radiology (T.D.B., C.D.), Institut Gustave Roussy, 94805 Villejuif Cedex, France
Address all correspondence and requests for reprints to: Martin Schlumberger, Institut Gustave Roussy, rue Camille Desmoulins, 94805 Villejuif Cedex, France. E-mail: schlumbg{at}igr.fr.
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Abstract |
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Aims: The aim of our study was to evaluate the impact of liver transarterial chemoembolization (TACE) in MTC patients with predominant and progressive liver metastases.
Patients and Methods: Twelve MTC patients underwent 18 TACE courses (mean, 1.5; range, 1–2). Response evaluation criteria in solid tumors were used to evaluate tumor responses. Symptomatic responses were defined by more than a 25% decrease of symptoms intensity.
Results: Partial radiological tumor response was obtained in five patients (42%) with a median duration of 17 months (mean, 19; range, 15–28 months), stabilization in five (42%) with a median duration of 24 months (mean, 24; range, 4–39 months), and progression in the remaining two (16%). The five partial tumor responses were observed in the nine patients with less than 30% liver involvement. Clinical response was observed in two of the five patients with diarrhea. Carcinoembryonic antigen did not appear to be a useful marker in this setting. Significant grade 3–4 toxicity was observed in one patient who had a major tumor necrosis after TACE.
Conclusion: TACE should be considered for treating MTC patients with progressive and predominant liver metastasis, and preferably at an early stage during the course of metastatic disease.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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MTC is a well-differentiated neuroendocrine tumor, and MTC patients with distant metastases have been treated with cytotoxic drugs demonstrated to be active in well-differentiated gastroentero pancreatic (GEP) neuroendocrine tumors. In MTC patients, various combinations of doxorubicin, 5-fluorouracil, dacarbazine, streptozocin, cyclophosphamide, and vincristine have produced response rates around 20% with symptomatic improvement in some; all responses were partial and transient, and no benefit on survival was demonstrated (4, 5, 6, 7, 8, 9, 10, 11). Diarrhea is incompletely controlled by loperamide, and somatostatin analogs and interferon are poorly effective to control symptoms (11, 12).
In some patients with metastatic MTC, the liver is the predominant localization of the disease. Because metastases are multiple, surgery and local ablative therapies such as radiofrequency, laser, or ethanol injection may provide some degree of palliation, but with no chance of complete eradication (13, 14). In the case of liver metastases from GEP endocrine tumors, embolization or chemoembolization has proven efficient for the control of both symptoms and tumor masses (15). Furthermore, this procedure has been reported effective in anecdotal MTC patients (16), and during the submission of this manuscript, a study on 11 patients with liver metastases from MTC reported symptomatic improvement in all patients, with transient remission or stabilization in 60% (17).
This technique allows the delivery of chemotherapy and embolic material through the hepatic artery to either a part or to the whole liver and limits the exposure of the body to the cytotoxic agents, thereby reducing its toxicity. Treatment can be repeated a number of times. Because of the low response rate of MTC to systemic treatment modalities and the similarities between MTC and GEP endocrine tumors, 12 MTC patients with predominant and progressive liver metastases were prospectively treated at our institution with chemoembolization.
In this report, we evaluated the toxicity and the response rate to chemoembolization of symptoms, tumor masses, and serum CEA levels in these 12 patients.
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Patients and Methods |
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Between March 2000 and July 2004, 12 MTC patients with predominant liver metastases were treated with chemoembolization (Table 1
). Eleven patients had sporadic MTC based on negative screening for germline RET mutation. One patient had familial MTC with RET mutation at codon 634, and a pheochromocytoma had been carefully excluded by urinary metanephrine measurement. Inclusion criteria were either liver metastases that progressed at a 6-month interval and/or that were associated with diarrhea that was not controlled by medical treatment with loperamide.
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Neck lymph nodes were present in six patients, and were associated with mediastinal lymph nodes in three; they were not submitted to surgery because they were asymptomatic and smaller in size than the multiple distant metastases to which they were associated. Retroperitoneal lymph node involvement was found in one patient. Lung or bone metastases were present in seven patients at the time of the study.
No hepatic metastasectomy or partial liver resection had been performed previously in any of these patients because metastases were multiple and diffuse in both lobes. Five patients had previously been treated with systemic chemotherapy with combinations of doxorubicin, 5 fluorouracil, streptozocin, and dacarbazine, and no objective response had been observed (10, 11); the period of time between the termination of chemotherapy and surgery ranged between 6 and 36 months.
This study was approved by our local scientific committee, and all patients gave their signed informed consent
Chemoembolization methods
Transarterial chemoembolization (TACE) of the hepatic artery was performed through a femoral access using a 5 French catheter with its tips placed in the common hepatic artery. Additionally, a coaxial 3 French catheter was used when needed for superselective catheterization. A portogram was first obtained by superior mesenteric artery injection of contrast medium and confirmed patency of the portal trunk and intrahepatic portal branches, and then TACE of the hepatic artery was undertaken. An angiogram of the hepatic artery was first obtained to serve as a map to guide the TACE. If the liver tumor involvement was less than 30%, TACE of the complete liver was performed, and if tumor liver involvement was over 30%, selective TACE of one side of the liver was performed. For each single course of TACE, the cytotoxic agent (doxorubicin 50–70 mg/treatment) was mixed with 10 ml of iodized oil (Lipiodol; Guerbet, Aulnay sous Bois, France) through a three-way stopcock to obtain a water-in-oil emulsion. After injection of the emulsion, if the targeted artery was still patent, embolization was performed using pledglets of gelfoam until complete blood flow stagnation. In case of selective TACE, the contralateral liver was treated 1–3 months later, according to the tolerance of the first TACE session.
A course is considered one session of TACE. A cycle consists of two courses of TACE delivered within 3 months either to treat repeatedly the whole liver or to treat successively both parts of the liver.
Response to treatment after one cycle was defined according to response evaluation criteria in solid tumors (RECIST) and was based on computed tomography performed at 1 and 3 months and then every 6 months, without and with contrast enhancement or on magnetic resonance imaging findings. Target lesions were specified at the time of study enrollment; all measurable lesions (larger than 10 mm in their largest diameter) up to 10 were used for response evaluation. In the case of disease progression, treatment was discontinued. In the case of tumor response or stabilization, TACE was not performed again until disease progression occurred, at which time a new cycle of TACE was undertaken.
Clinical response was defined as the decrease by more than 25% of the number of stools per day. Biological response was defined as the decrease by more than 25% of the CEA level.
Toxicity was defined according to World Health Organization recommendations
Assays
CT was measured using the ELSA-CT kit (Cis-Bio International, Gif-sur-Yvette, France; normal <10 pg/ml), and CEA was measured using the Enzymum-test CEA kit (Boehringer, Mannheim, Germany; normal < 7 ng/ml).
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Initially, a total of 18 courses (mean, 1.5; range, 1–2 per patient) of TACE were performed and were delivered during 12 cycles between March 2000 and July 2004. They were technically successful in all cases. However, in five courses, due to severe slowing down of the blood flow induced by the injection of the drug/Lipiodol emulsion, TACE consisted only in the injection of the drug/Lipiodol emulsion without embolization, because we considered that dwell time between drug and tumor was significantly increased.
Toxicity
After embolization, all patients experienced symptoms (nausea, vomiting, abdominal pain, fever) that were usually mild and transient (grade 1), together with elevation of liver enzymes that normalized within 5–10 d. One patient (case 5) developed a major postembolization tumor necrosis, with fever and pain (grade 3) that lasted for 8 d and resolved with symptomatic treatments. Hospitalization lasted between 6 and 10 d after embolization.
Clinical response
Clinical response was observed in two of the five patients with diarrhea; these two patients also experienced a morphological tumor response.
Biological response
A decrease of more than 25% of CEA level was observed in four patients, two with a partial morphological response, one with stable disease, and one with progressive disease. Among the five patients with an increase in CEA levels of more than 25%, three had a morphological liver response and two had a stable liver disease, but all had disease progression in other locations. CT levels fluctuated by 30–50% at short time intervals and, for this reason, could not be taken into account for the assessment of response to therapy (1, 2).
Radiological response
Partial morphological response, according to RECIST criteria, was obtained in five patients (42%) and lasted for a median of 17 months (mean, 19 months; range, 15–28 months). A stabilization that was observed in five patients (42%) lasted for a median of 24 months (mean, 24 months; range, 4–34 months), and disease progression occurred in the remaining two patients (16%). In patients who experienced an objective response, a 70% mean decrease of tumor masses (range, 48–97%) was observed, but there was no complete tumor response; in these patients the absence of new lesion was assessed by hepatic arteriography, which was always the first step of TACE, or at the arterial phase on computed tomography.
Morphological response was related to the initial extent of hepatic involvement (Table 1
): in the nine patients with liver involvement less than 30%, partial response was observed in five, stabilization in two, and disease progression in two patients. In contrast, only stable disease was observed in the three patients with a liver involvement between 30 and 50%. The response to TACE was not related to the size of the larger liver metastases.
Repetition of TACE
One year after the first TACE cycle, three patients (patients 6, 9, and 10) who experienced a partial response after the first TACE cycle underwent another TACE cycle, with two courses per cycle, and a partial tumor response was obtained in these three patients, but its duration was shorter than after the first cycle, being 3, 3, and 9 months, respectively; among these three patients, one patient (patient 10) underwent a third TACE cycle, but liver disease continued to progress.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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In this study of 12 MTC patients with liver metastases, we observed after chemoembolization a much higher tumor response rate (42% partial responses and 42% stabilizations) than with systemic chemotherapy (<20%). Tumor response was evaluated according to RECIST criteria, and this may lead to underestimating the actual response rate, because tumor response may consist only in tumor devascularization without significant changes in tumor volume. Except in one patient, toxicity was mild and transient. This may be related to the low intensity of TACE with a mean number of 1.5 courses per patient, which may both preserve arterial patency and limit liver toxicity. Indeed, a pheochromocytoma has been reported as a cause of death after TACE and should be carefully excluded by biological screening before TACE (18).
The extent of liver involvement was the main factor that influenced the chemoembolization results, with partial responses being observed only in patients with limited liver involvement. These figures are in close agreement with experience gained in patients with liver metastases from GEP neuroendocrine tumors, for which embolization or chemoembolization is even more effective when liver involvement is less than 30% and when metastases are smaller than 30 mm (19, 20, 21). In the present study, the size of metastases did not influence the tumor response, but this may be related to the limited number of patients. After a single TACE cycle, duration of partial responses was longer than 1 yr and duration of stabilization in four of five patients was also longer than 1 yr. Furthermore, more than 1 yr after the first TACE, another TACE cycle in three patients in whom progression occurred produced again a partial tumor response, but of a shorter duration. However, despite favorable responses, TACE did not allow for curative surgery that is probably not possible in these patients with diffuse hepatic involvement.
Each course of TACE required a hospitalization of 6–10 d. Indeed, except in one patient who developed tumor necrosis rapidly after TACE, the toxicity was mild, and an earlier discharge from the hospital with subsequent outpatient monitoring is probably feasible without compromising safety after uneventful TACE.
Furthermore, an improvement in diarrhea was observed in two of the five patients, and this indeed improved their quality of life. Finally, CEA did not appear to be a useful tumor marker in this setting, because CEA levels depend on tumor response and on the behavior of the other tumor foci.
In conclusion, these data clearly confirm the interest in chemoembolization for the treatment of liver metastases, in agreement with a recent report (17). Its efficiency is higher in patients with limited liver involvement and may be improved by the use of other cytotoxic agents.
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Footnotes |
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First Published Online April 11, 2006
Abbreviations: CEA, Carcinoembryonic antigen; CT, calcitonin; GEP, gastroentero pancreatic; MTC, medullary thyroid carcinoma; RECIST, response evaluation criteria in solid tumors; TACE, transarterial chemoembolization.
Received November 3, 2005.
Accepted April 3, 2006.
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References |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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