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Transcatheter Arterial Chemoembolization for Liver Metastases in Patients with Adrenocortical Carcinoma
Transcatheter Arterial Chemoembolization for Liver Metastases in Patients with Adrenocortical Carcinoma Julien Cazejust, MD, Thierry De Baère, MD, Anne Auperin, MD, Frédéric Deschamps, MD, Lukas Hechelhammer, MD, Mohamed Abdel-Rehim, MD, Martin Schlumberger, PhD, Sophie Leboulleux, MD, and Eric Baudin, MD
PURPOSE: To retrospectively evaluate the effectiveness, tolerance, and predictors of response to transcatheter arterial chemoembolization for treatment of liver metastases from adrenocortical carcinoma. MATERIALS AND METHODS: Twenty-nine patients with progressive liver metastases from adrenocortical carcinoma were treated with transcatheter arterial chemoembolization. Rate and duration of tumor response were defined according to Response Evaluation Criteria In Solid Tumors. The size of liver metastases, percentage of liver involvement, and Lipiodol uptake were studied as potential predictive factors of response. Time to liver and metastatic lesion progression were considered as endpoints. RESULTS: Three months after transcatheter arterial chemoembolization, a liver morphologic response was observed in six of 29 patients (21%), stabilization in 18 (62%), and progression in five (17%). According to per-lesion analysis (n ⴝ 103), a morphologic response was observed in 23 lesions (22%), stabilization in 67 (65%), and progression in 13 (13%). Higher response rates were observed in cases in which the diameter of the target metastasis was 3 cm or smaller (P ⴝ .002) and in cases of high Lipiodol uptake (> 50%; P < .0001). On per-patient and per-lesion bases, progression rates were 32% and 55% at 6 months and 23% and 38% at 12 months. The median time to progression was 9 months and median survival was 11 months after the first procedure. CONCLUSIONS: Transcatheter arterial chemoembolization should be considered as part of the therapeutic arsenal to treat liver metastases from adrenocortical carcinoma. The size of liver metastases and the percentage of Lipiodol uptake may help identify patients likely to benefit most from transcatheter arterial chemoembolization. J Vasc Interv Radiol 2010; 21:1527–1532 Abbreviation:
RECIST ⫽ Response Evaluation Criteria In Solid Tumors
ADRENOCORTICAL carcinoma is a rare and highly malignant neoplasm that may portend a poor prognosis (1,2). Complete surgical resection is the only curative treatment for local disease. However, local recurrence or
From the Department of Interventional Radiology, Institut Gustave Roussy, 39 Rue Camille Desmoulins, Villejuif 94805, France. Received September 22, 2008; final revision received May 18, 2010; accepted May 25, 2010. Address correspondence to T.D.B.; E-mail: [email protected] None of the authors have identified a conflict of interest. © SIR, 2010 DOI: 10.1016/j.jvir.2010.05.020
distant metastases occur in more than 50% of patients (3–5). Patients with metastatic disease have limited therapeutic options, and 5-year survival rates were reported to be less than 15% in recent series (1,2,6 – 8). Systemic chemotherapy or adrenolytic agents such as cisplatin or mitotane constitute historical therapies that yield a 30% response rate at most, with a doubtful impact on survival (1,2,9 – 11). Monitoring of plasma mitotane levels (12,13) and analysis of expression of the excision repair cross-complementation group-1 protein on tumor tissue may help predict a percentage of responders above 30% to these therapies but require further validation (14).
Even given this progress, new therapeutic options are desperately needed. Preliminary results concerning new topoisomerase type 1 or epidermal growth factor receptor inhibitors combined with gemcitabine have recently demonstrated very limited antitumor activity (15–17). More recently, the preliminary results of molecular targeting of insulin-like growth factor 1 receptor have been published and appear promising (18 –20). However, reports of complete response in metastatic adrenocortical carcinoma are still lacking. Along with efforts to develop new therapeutic strategies, well known techniques such as chemoembolization could be studied in adrenocor-
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Chemoembolization for Liver Metastases in Adrenocortical Carcinoma
tical carcinoma, possibly in combination with other well known treatments such as mitotane while awaiting more effective agents. Distant metastases are the main cause of adrenocortical carcinoma– related death, and the liver is one of the most common sites of metastases (1,2,6 –9,21). Liver transcatheter arterial chemoembolization has been demonstrated to achieve significant antitumor activity in several cancers. Indeed, transcatheter arterial chemoembolization is widely used for the treatment of hepatocellular carcinoma (22) and liver metastases from neuroendocrine tumors (23–25). As in neuroendocrine tumor, the potential indications for transcatheter arterial chemoembolization may be twofold in adrenocortical carcinoma, namely the control of liver metastases and of hormone secretions. We undertook a single-center retrospective study to obtain insights into the tolerance and efficacy of transcatheter arterial chemoembolization in patients with progressive liver metastases from adrenocortical carcinoma. In addition, we investigated predictors of response to transcatheter arterial chemoembolization.
MATERIALS AND METHODS Inclusion Criteria and Patient Characteristics Ninety-one consecutive patients with metastatic adrenocortical carcinoma were treated in a single institution between 1995 and 2005. Data concerning 29 consecutive patients (23 women and six men; median age, 41 years; age range, 15–71 y) with progressive liver metastases from adrenocortical carcinoma treated with transcatheter arterial chemoembolization from June 1995 to August 2005 were retrospectively reviewed. The other 62 patients were not treated with transcatheter arterial chemoembolization because liver involvement was not considered to represent the predominant site of metastases. Our study was approved by our institutional review board, and the requirement for informed consent was waived. All patients had pathologically confirmed adrenocortical carcinoma. At that time, criterion for transcatheter arterial chemoembolization in our center was progression of liver metastases documented by two
consecutive abdominal computed tomography (CT) scans in patients with isolated or predominant liver metastases. Sixteen patients (55%) had associated hormonal secretion (cortisol secretion, n ⫽ 9; androgen secretion, n ⫽ 6; multiple secretions, n ⫽ 1). Progressive disease was demonstrated after treatment with mitotane alone (n ⫽ 2), after mitotane plus one type of cytotoxic chemotherapy (n ⫽ 19), or after mitotane plus two or more types of cytotoxic chemotherapy (n ⫽ 8), including cisplatin-based chemotherapy. In these 29 patients, mitotane levels at the time of transcatheter arterial chemoembolization were within the therapeutic range (ie, ⬎ 14 mg/L) in 17 patients, below this threshold in eight patients, and not measured in four patients. At the time of the best transcatheter arterial chemoembolization response, mitotane levels were not significantly modified compared with the level at inclusion date. No liver resection had previously been performed in any of these patients. When transcatheter arterial chemoembolization was performed, all patients received no systemic chemotherapy except mitotane. At the time of transcatheter arterial chemoembolization, 22 patients had lung metastatic lesions, five had bone metastatic lesions, and six had lymph node metastatic lesions. One patient had skin, ovarian, cerebral, and thyroid metastatic lesions. These 29 patients had a total of 103 liver metastatic lesions. Each patient had one to five liver metastases (mean, 3.6). The maximum diameter of metastatic lesions before transcatheter arterial chemoembolization ranged from 1.0 cm to 14.5 cm (mean, 3.8 cm). Fifty-four metastases measured 3 cm or less and 49 more than 3 cm in largest diameter. Tumor involvement of the liver was less than 30% in eight patients, 30%–50% in 12 patients, and more than 50% in nine patients. Chemoembolization Methods Transcatheter arterial chemoembolization of the liver was performed under local anaesthesia via a femoral access with the use of a 5-F catheter. A portogram was first obtained after injection of contrast medium into the superior mesenteric artery to assess patency of the portal trunk and intrahepatic portal
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branches. Then, a 5-F catheter was placed in the common hepatic artery to obtain an angiogram, which was used to plan the transcatheter arterial chemoembolization. A transcatheter arterial chemoembolization course comprised one injection of the drug plus embolic material. Tumors invading only one lobe or tumors invading both lobes with a tumor burden less than 30% were treated in a single session targeting one or two lobes, respectively. If tumors invaded both lobes and exhibited a tumor burden of more than 30%, two treatments targeting one lobe after the other were scheduled 1–3 months apart according to tolerance of the first chemoembolization session. For each single course of transcatheter arterial chemoembolization, the cytotoxic agent (cisplatin 1–2 mg/kg) was mixed with 10 mL of iodized oil (Lipiodol; Laboratoire Andre 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 with 1–3-mm pledgets of gelatin sponge (Hemocol; Medical Biomaterial Products, Neustadt-Glewe, Germany) until total stagnation of blood flow was achieved. Each patient received hydration (2 L per 24 h) beginning the day before chemoembolization. Antibiotics (-lactamin and clavulanate 2 g/d) and antiemetic drugs (ondansetron) were administered and hydration was maintained over a period of 2 days after the chemoembolization procedure. Evaluation Criteria The rate and duration of tumor response were defined according to Response Evaluation Criteria In Solid Tumors (RECIST) exclusively applied to liver metastases (26): a partial response was defined as a decrease of 30% or more in size of the tumor and progressive disease as an increase of 20% or more in size; otherwise the response was classified as stable (including minor response for tumor decreasing ⬍ 30%). Serial CT or magnetic resonance (MR) images were obtained with or without injection of contrast medium at 1 and 3 months and then every 3 months after each course of therapy and were used to measure tumor response. We measured the longest diameter of each metastasis and compared it versus baseline measure-
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ments for per-lesion analysis and the sum of the diameters of all metastases for the per-liver analysis. We evaluated the following as potential predictors of response: size of hepatic metastatic lesions (ⱕ 3 cm vs ⬎ 3 cm), extent of Lipiodol uptake after chemoembolization (⬍ 50% vs ⬎ 50% of surface area of metastases on first follow-up CT), and percentage of liver involvement (⬍ 30%, 30%–50%, and ⬎ 50%). Liver enzyme and creatinine levels were routinely monitored. Toxicity was assessed and graded according to the Common Terminology Criteria for Adverse Events, version 3.0 (27). No patient was lost to follow-up until disease progression or death had been documented. Statistical Methods Association was sought between morphologic response and time to progression after transcatheter arterial chemoembolization (evaluated on CT at 3 months after initial chemoembolization) and the following parameters: extent of liver involvement, tumor size, and degree of Lipiodol uptake in each metastasis. The Fisher exact test or 2 test was used for univariate analysis, and logistic regression was used for multivariate analysis. Time to progression was defined as the time between the first transcatheter arterial chemoembolization course and the progression of liver metastases (for per-liver analysis) or each metastatic lesion (for per-lesion analysis) or death. In the absence of progression, the last CT scan was considered for analysis. Extrahepatic progression was not analyzed. The incidence of progression was estimated as 1 minus the Kaplan-Meier estimate. The 95% CIs of actuarial rates were calculated with the Rothman method. Survival was defined as the time between the first chemoembolization procedure and death from any cause or the last follow-up contact for patients who were alive.
RESULTS Chemoembolization A total of 50 courses were attempted between June 1995 and August 2005 that resulted in 45 chemoembolization procedures; three patients underwent only embolization (without chemotherapy) be-
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Figure 1.
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Survival after the first course of transcatheter arterial chemoembolization.
cause of the potential risk of renal toxicity in two and previous allergy to cisplatin in one. In two cases, severe arterial spasm induced by the injection of the drug/Lipiodol emulsion during the first transcatheter arterial chemoembolization session precluded embolization. The patients received one to five courses of therapy (mean, 1.7): 16 patients had one course, eight had two courses, three had three courses, one had four courses, and one had five courses. Transcatheter arterial chemoembolization was technically successful in all cases except in two patients with arterial spasms. Morphologic Response: Progression Three months after transcatheter arterial chemoembolization, per-patient analysis showed a morphologic response in six patients (21%), stabilization in 18 (62%), and progression in the remaining five (17%). Therefore, a clinical benefit (ie, response or disease stabilization) was observed in 83% of these patients (ie, 24 of 29). In the perlesion analysis, among 103 liver metastatic lesions, 23 (22%) exhibited a partial response, 23 (22%) a minor response, 44 (43%) stabilization, and 13 (13%) progression. No delayed response (ie, “tumor improvement”) was observed after 3 months. The progression rates according to per-patient analysis were 32% (95% CI, 18%–51%) and 55% (95% CI, 34%– 74%) at 6 and 12 months, respectively. The progression rates according to perlesion analysis were 23% (95% CI, 16%– 33%) and 38% (95% CI, 27%–51%) at 6 and 12 months, respectively. Median
time to progression was 9 months (range, 1–19 months). Survival Median follow-up was 28 months. Median survival time was 11 months (range, 1.4 –31.9 months). Survival rates after the first chemoembolization session were 66% (95% CI, 47%– 80%) and 40% (95% CI, 24%–58%) at 6 and 12 months, respectively (Fig 1). The main cause of death was disease progression in 16 patients with liver (n ⫽ 8), lung (n ⫽ 4), or brain (n ⫽ 4) tumor progression. Other causes of death included sepsis (n ⫽ 2), renal insufficiency (n ⫽ 1), small bowel obstruction (n ⫽ 1), diffuse venous thrombosis (n ⫽ 1), and toxicity during subsequent systemic chemotherapy (n ⫽ 1). The cause of death was unknown in six patients: two had progressive disease on the last follow-up CT scan and four had stable disease. Four patients died during the first 3 months after chemoembolization, but none of the patients died as a consequence of the procedure. Predictors of Response At univariate analysis, a significant correlation was found between the per-lesion response to transcatheter arterial chemoembolization and the size of hepatic metastases (P ⫽ .002) and with the degree of Lipiodol uptake (P ⬍ .0001; Table). Interestingly, Lipiodol uptake was correlated with smaller tumor size (P ⫽ .0004). Indeed, 47 of 54 liver metastases smaller than 3 cm in diameter (64%) had Lipiodol up-
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Tumor Response According to Tumor Size and Lipiodol Uptake in 103 Liver Metastases Metastasis Size*
Lipiodol Uptake†
Outcome
ⱕ 3 cm
⬎ 3 cm
ⱕ 50%
⬎ 50%
Overall
Partial response Minor response Stable disease Progressive disease Overall
17/64 (31) 13/64 (24) 23/64 (43) 1/64 (2) 64
6/49 (12) 10/49 (20) 21/49 (43) 12/49 (24) 49
2/33 (6) 3/33 (9) 16/33 (48) 12/33 (36) 33
21/70 (30) 20/70 (29) 28/70 (40) 1/70 (1) 70
23 23 44 13 103
Note.—Values in parentheses are percentages. * P ⫽ .002 between groups. † P ⬍ .0001 between groups (2 test).
Figure 2.
Time to progression according to tumor size.
Figure 3.
Time to progression according to Lipiodol uptake in liver metastases.
take exceeding 50%, compared with only 25 of 49 larger than 3 cm in diameter (36%). On multivariate analysis (ie, logistic regression), response to chemoembolization remained independently associated with tumor size (⬍ 3 cm; P ⫽ .05) and Lipiodol uptake (⬎ 50%; P ⫽ .003). Shorter time to per-lesion progression
was associated with liver metastases that were larger than 3 cm and Lipiodol uptake lower than 50% (P ⫽ .008 and P ⬍ .0001, respectively; Figs 2, 3). On multivariate analysis, larger tumor size and lack of Lipiodol uptake remained significantly associated with shorter time to progression (P ⫽ .01 and P ⬍ .0001, respectively). Six- and 12-month pro-
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gression rates of metastases smaller than 3 cm were both 11% and were 37% and 74%, respectively, for metastases larger than 3 cm. Six and 12-month progression rates of metastases with Lipiodol uptake greater than 50% were 7% and 10%, respectively, and were 57% and 100%, respectively, for metastases with Lipiodol uptake lower than 50%. Toxicity After transcatheter arterial chemoembolization, 18 patients (62%) had nausea and vomiting, including 13 grade 1 episodes (45%) and five grade 2 episodes (17%) (27). Seventeen patients (59%) had abdominal pain: 10 (34%) grade 1, four (14%) grade 2, and 3 (10%) grade 3. These symptoms were controlled with antalgic drugs (eg, paracetamol or opioid derivatives). Among these 17 patients, two had symptoms that lasted 5 days, including grade 3 fever and abdominal pain, which were controlled with symptomatic treatments and antibiotics. Major postembolization tumor necrosis (ie, hypodensity of tumor and no enhancement after contrast medium injection) was demonstrated on CT in the two patients with prolonged symptoms. No significant relationship was found between fever after transcatheter arterial chemoembolization and the extent of liver involvement. However, a trend was noted because fever was observed after chemoembolization in 13% of patients with liver involvement of less than 30% (one of eight), and in 42% of patients with liver involvement exceeding 30% (nine of 21). After the procedure, grade 1, 2, or 3 liver toxicities occurred in 69% (n ⫽ 20), 24% (n ⫽ 7), and 7% (n ⫽ 2) of patients, respectively, and normalized within 4 –10 days in all patients. No renal toxicity occurred. Hospitalization lasted from 3 to 6 days (mean, 4.6 d; range, 3– 6 d) after chemoembolization. No procedure-related mortality was observed after the procedure. At the time of the best chemoembolization response, mitotane levels did not significantly change compared with levels at the inclusion date.
DISCUSSION In cases of adrenocortical carcinoma with metastases, the number of metastatic organs and the mitotic in-
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dex were recently highlighted as exerting a major prognostic impact (7). In addition, in these patients, the liver is one of the two most frequent sites of distant metastases, together with the lung, and frequently the first site involved (6 – 8). Most liver tumors— especially highly arterialized tumors, such as hepatocellular carcinoma or neuroendocrine tumors metastases— are reported to have nearly 100% of blood inflow from the hepatic artery. This preferential arterial feeding probably explains the favorable results reported with intraarterial treatment such as transcatheter arterial chemoembolization. The fact that liver metastases from adrenocortical carcinoma exhibit hypervascular patterns signified that transcatheter arterial chemoembolization could be considered as a promising antitumor tool in this group of endocrine tumors. This hypervascularized feature of adrenocortical carcinoma also supports the use of angiogenesis inhibitors in these patients. Patients with adrenocortical carcinoma with isolated or predominant liver metastases were enrolled in the present study because we consider liver progression to be a significant cause of death. This was true even in one patient with diffuse metastases, including cerebral metastases, which were stabilized with external radiation therapy. In our experience, transcatheter arterial chemoembolization demonstrated a 83% rate of tumor control, including 21% objective responses and a 62% stabilization rate in patients with adrenocortical carcinoma. More importantly, the duration of liver responses exceeded 6 and 12 months in 68% and 45% of patients, respectively, allowing them to attain an 11-month median survival time. In addition, an even higher rate of long-term tumor control was observed in patients with adrenocortical carcinoma with liver metastases smaller than 3 cm, as 89% were nonprogressive 12 months after transcatheter arterial chemoembolization, including a 31% incidence of partial response. As all patients with adrenocortical carcinoma had progressive disease at the time of study entry and no other systemic antitumor therapy but mitotane was given during chemoembolization, these preliminary results are encouraging even if they are limited to the liver. Indeed, these results compared
Cazejust et al favorably with the 4-month maximum progression-free survival time obtained with irinotecan or the 5.5-month median survival time reported with the erlotinib/gemcitabine combination in two previous third-line adrenocortical carcinoma studies (16,17). It is noteworthy that none of the patients who had a mitotane level lower than the therapeutic threshold at study initiation experienced an increase of mitotane level within the therapeutic range during study evaluation. Of course, only a future randomized study combining, for instance, systemic chemotherapy with or without liver transcatheter arterial chemoembolization will definitely determine the place of this new tool in the therapeutic arsenal against adrenocortical carcinoma. Metastases from adrenocortical carcinoma smaller than 3 cm had a higher Lipiodol uptake and exhibited a better objective response rate (P ⬍ .0001). A trend was also found between the percentage of liver involvement and partial response, as five of six patients who showed a partial response had liver involvement of less than 50%; this was also reported by our group in neuroendocrine tumors (28). Taken together, these results prompt us to propose transcatheter arterial chemoembolization early in the course of the disease, as soon as liver metastases are detected. The aggressiveness of most adrenocortical carcinoma in contrast with well differentiated neuroendocrine carcinoma also supports this proposal. In addition, our results suggest that the percentage of Lipiodol uptake may help predict liver metastases likely to respond to this therapeutic option. Postembolic syndrome, including transient abdominal pain, fever, nausea, and liver enzyme elevation, was frequently observed after transcatheter arterial chemoembolization (38 of 50 courses; 76%), and was below grade 2 in the majority of patients. In four patients (five of 50 courses), severe postembolization syndrome occurred. Fever occurred more frequently when tumors were large, probably because of a larger volume of induced tumor necrosis (trend, P ⫽ .20, Fisher test). Two of the four patients who had severe postembolization syndrome with fever and abdominal pain for 7 days had substantial tumor necrosis on CT. The other two had severe postembolization syndrome 2 and 4 days, respec-
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tively, so no CT scan was obtained for these patients. This also argues in favor of early treatment when the tumor volume is small. Otherwise, in patients with extensive disease, the liver should be treated in several sessions to decrease toxicity. We used chemoembolization with cisplatin, a Lipiodol emulsion, and gelatin sponge pledgets in 90% of the procedures because chemoembolization was demonstrated to be superior to chemotherapy with Lipiodol or embolization alone in hepatocellular carcinoma (22,29). The same holds true for liver metastases from islet cell tumors; adding intraarterial chemotherapy to hepatic arterial embolization improves outcome, with response rates of 50% and 25% for transcatheter arterial chemoembolization and embolization alone, respectively (24). New embolic agents loaded with drugs that have recently been used successfully in hepatocellular carcinoma (30) or neuroendocrine tumors (31) might further improve treatment efficacy and lower the risk of systemic side effects. Indeed, pharmacokinetic studies in animals (32) and humans (30) have demonstrated a 10-fold reduction of systemic peak drug concentration when such drug-eluting beads were compared with conventional intraarterial chemoembolization with a drug/ Lipiodol mixture and gelatin sponge pledgets (30,32), as applied in this study, suggesting that drug was more concentrated in the liver (and therefore in the liver metastases). However, only one of these studies was randomized (26), making the interest of combining cytotoxic chemotherapy with embolization still a matter of discussion. Therefore, whether such loadable embolic material may further improve the efficacy of intraarterial treatments in the future remains to be demonstrated. To date, platinum-derived drugs, the most efficient systemic drugs in adrenocortical carcinoma, cannot be loaded efficiently, and doxorubicin or irinotecan are the only loadable products. However, the role of doxorubicin or irinotecan as effective antitumor agents in adrenocortical carcinoma respectively continues to be challenged (33) or is considered poor (15). The major limitations of the present study are the small size and the heterogeneity of the study group. The limited size is related to the extreme rarity
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of the disease. The heterogeneity is a result of the use of transcatheter arterial chemoembolization at different times after the diagnosis of liver metastases, often after two or three lines of systemic chemotherapy. The first patients in our series received transcatheter arterial chemoembolization for advanced liver disease (before 2000), but more recently (since 2000), we performed transcatheter arterial chemoembolization earlier during the course of liver metastases. Cumulative response was observed in 83% patients at 3 months after chemoembolization, with a median time to progression of 9 months, indicated that transcatheter arterial chemoembolization is a new tool to be included in the therapeutic arsenal to treat adrenocortical carcinoma. Early treatment when liver metastases are smaller than 3 cm should be preferred. References 1. Gicquel C, Baudin E, Lebouc Y, Schlumberger M. Adrenocortical carcinoma. Ann Oncol 1997; 8:423– 427. 2. Allolio B, Fassnacht M. Adrenocortical carcinoma: clinical update. J Clin Endocrinol Metab 2006; 91:2027–2037. 3. Weiss LM. Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors. Am J Surg Pathol 1984; 8:163–169. 4. Weiss LM, Medeiros LJ, Vickery AL Jr. Pathologic features of prognostic significance in adrenocortical carcinoma. Am J Surg Pathol 1989; 13:202–206. 5. Gicquel C, Bertagna X, Gaston V, et al. Molecular markers and long-term recurrences in a large cohort of patients with sporadic adrenocortical tumors. Cancer Res 2001; 61:6762–2767. 6. Abiven G, Coste J, Groussin L, et al. Clinical and biological features in the prognosis of adrenocortical cancer: poor outcome of cortisol-secreting tumors in a series of 202 consecutive patients. J Clin Endocrinol Metab 2006; 91:2650 –2655. 7. Assie G, Antoni G, Tissier F, et al. Prognostic parameters of metastatic adrenocortical carcinoma. J Clin Endocrinol Metab 2007; 92:148 –154. 8. Berruti A, Terzolo M, Sperone P, et al. Etoposide, doxorubicin and cisplatin plus mitotane in the treatment of advanced adrenocortical carcinoma: a large prospective phase II trial. Endocr Relat Cancer 2005; 12:657– 666. 9. Ahlman H, Jansson S, Wangberg B, et al. Adrenocortical carcinoma– diagnostic and therapeutical implications. Eur J Surg 1993; 159:149 –158.
10. Schteingart DE, Doherty GM, Gauger PG, et al. Management of patients with adrenal cancer: recommendations of an international consensus conference. Endocr Relat Cancer 2005; 12: 667– 680. 11. Wooten MD, King DK. Adrenal cortical carcinoma. Epidemiology and treatment with mitotane and a review of the literature. Cancer 1993; 72:3145– 3155. 12. Baudin E, Pellegriti G, Bonnay M, et al. Impact of monitoring plasma 1,1-dichlorodiphenildichloroethane (o,p=DDD) levels on the treatment of patients with adrenocortical carcinoma. Cancer 2001; 92:1385–1392. 13. Haak HR, Hermans J, van de Velde CJ, et al. Optimal treatment of adrenocortical carcinoma with mitotane: results in a consecutive series of 96 patients. Br J Cancer 1994; 69:947–951. 14. Olaussen KA, Dunant A, Fouret P, et al. DNA repair by ERCC1 in nonsmall-cell lung cancer and cisplatinbased adjuvant chemotherapy. N Engl J Med 2006; 355:983–991. 15. Baudin E, Docao C, Gicquel C, et al. Use of a topoisomerase I inhibitor (irinotecan, CPT-11) in metastatic adrenocortical carcinoma. Ann Oncol 2002; 13: 1806 –1809. 16. Kirschner LS. Emerging treatment strategies for adrenocortical carcinoma: a new hope. J Clin Endocrinol Metab 2006; 91:14 –21. 17. Quinkler M, Hahner S, Wortmann S, et al. Treatment of advanced adrenocortical carcinoma with erlotinib plus gemcitabine. J Clin Endocrinol Metab 2008; 93:2057–2062. 18. Haluska P, Worden F, Olmos D, et al. Safety, tolerability, and pharmacokinetics of the anti-IGF-1R monoclonal antibody figitumumab in patients with refractory adrenocortical carcinoma. Cancer Chemother Pharmacol 2009; 65: 765–773. 19. Lindsay CR, Chan E, Evans TR, et al. Phase I dose escalation study of continuous oral dosing of OSI-906, an insulin like growth factor-1 receptor (IGF-1R) tyrosine kinase inhibitor, in patients with advanced solid tumors. Presented at the 45th Scientific Assembly of the American Society of Clinical Oncology; May 29 to June 2, 2009; Orlando, FL. 20. Lindsay CV, Downs CT, Brown M. Physiological variation in amethyst sunbirds (Chalcomitra amethystina) over an altitudinal gradient in winter. J Exp Biol 2009; 212:483– 493. 21. Brennan MF. Adrenocortical carcinoma. CA Cancer J Clin 1987; 37:348 – 365. 22. Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoem-
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PURPOSE: To retrospectively evaluate the effectiveness, tolerance, and predictors of response to transcatheter arterial chemoembolization for treatment of liver metastases from adrenocortical carcinoma. MATERIALS AND METHODS: Twenty-nine patients with progressive liver metastases from adrenocortical carcinoma were treated with transcatheter arterial chemoembolization. Rate and duration of tumor response were defined according to Response Evaluation Criteria In Solid Tumors. The size of liver metastases, percentage of liver involvement, and Lipiodol uptake were studied as potential predictive factors of response. Time to liver and metastatic lesion progression were considered as endpoints. RESULTS: Three months after transcatheter arterial chemoembolization, a liver morphologic response was observed in six of 29 patients (21%), stabilization in 18 (62%), and progression in five (17%). According to per-lesion analysis (n ⴝ 103), a morphologic response was observed in 23 lesions (22%), stabilization in 67 (65%), and progression in 13 (13%). Higher response rates were observed in cases in which the diameter of the target metastasis was 3 cm or smaller (P ⴝ .002) and in cases of high Lipiodol uptake (> 50%; P < .0001). On per-patient and per-lesion bases, progression rates were 32% and 55% at 6 months and 23% and 38% at 12 months. The median time to progression was 9 months and median survival was 11 months after the first procedure. CONCLUSIONS: Transcatheter arterial chemoembolization should be considered as part of the therapeutic arsenal to treat liver metastases from adrenocortical carcinoma. The size of liver metastases and the percentage of Lipiodol uptake may help identify patients likely to benefit most from transcatheter arterial chemoembolization. J Vasc Interv Radiol 2010; 21:1527–1532 Abbreviation:
RECIST ⫽ Response Evaluation Criteria In Solid Tumors
ADRENOCORTICAL carcinoma is a rare and highly malignant neoplasm that may portend a poor prognosis (1,2). Complete surgical resection is the only curative treatment for local disease. However, local recurrence or
From the Department of Interventional Radiology, Institut Gustave Roussy, 39 Rue Camille Desmoulins, Villejuif 94805, France. Received September 22, 2008; final revision received May 18, 2010; accepted May 25, 2010. Address correspondence to T.D.B.; E-mail: [email protected] None of the authors have identified a conflict of interest. © SIR, 2010 DOI: 10.1016/j.jvir.2010.05.020
distant metastases occur in more than 50% of patients (3–5). Patients with metastatic disease have limited therapeutic options, and 5-year survival rates were reported to be less than 15% in recent series (1,2,6 – 8). Systemic chemotherapy or adrenolytic agents such as cisplatin or mitotane constitute historical therapies that yield a 30% response rate at most, with a doubtful impact on survival (1,2,9 – 11). Monitoring of plasma mitotane levels (12,13) and analysis of expression of the excision repair cross-complementation group-1 protein on tumor tissue may help predict a percentage of responders above 30% to these therapies but require further validation (14).
Even given this progress, new therapeutic options are desperately needed. Preliminary results concerning new topoisomerase type 1 or epidermal growth factor receptor inhibitors combined with gemcitabine have recently demonstrated very limited antitumor activity (15–17). More recently, the preliminary results of molecular targeting of insulin-like growth factor 1 receptor have been published and appear promising (18 –20). However, reports of complete response in metastatic adrenocortical carcinoma are still lacking. Along with efforts to develop new therapeutic strategies, well known techniques such as chemoembolization could be studied in adrenocor-
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Chemoembolization for Liver Metastases in Adrenocortical Carcinoma
tical carcinoma, possibly in combination with other well known treatments such as mitotane while awaiting more effective agents. Distant metastases are the main cause of adrenocortical carcinoma– related death, and the liver is one of the most common sites of metastases (1,2,6 –9,21). Liver transcatheter arterial chemoembolization has been demonstrated to achieve significant antitumor activity in several cancers. Indeed, transcatheter arterial chemoembolization is widely used for the treatment of hepatocellular carcinoma (22) and liver metastases from neuroendocrine tumors (23–25). As in neuroendocrine tumor, the potential indications for transcatheter arterial chemoembolization may be twofold in adrenocortical carcinoma, namely the control of liver metastases and of hormone secretions. We undertook a single-center retrospective study to obtain insights into the tolerance and efficacy of transcatheter arterial chemoembolization in patients with progressive liver metastases from adrenocortical carcinoma. In addition, we investigated predictors of response to transcatheter arterial chemoembolization.
MATERIALS AND METHODS Inclusion Criteria and Patient Characteristics Ninety-one consecutive patients with metastatic adrenocortical carcinoma were treated in a single institution between 1995 and 2005. Data concerning 29 consecutive patients (23 women and six men; median age, 41 years; age range, 15–71 y) with progressive liver metastases from adrenocortical carcinoma treated with transcatheter arterial chemoembolization from June 1995 to August 2005 were retrospectively reviewed. The other 62 patients were not treated with transcatheter arterial chemoembolization because liver involvement was not considered to represent the predominant site of metastases. Our study was approved by our institutional review board, and the requirement for informed consent was waived. All patients had pathologically confirmed adrenocortical carcinoma. At that time, criterion for transcatheter arterial chemoembolization in our center was progression of liver metastases documented by two
consecutive abdominal computed tomography (CT) scans in patients with isolated or predominant liver metastases. Sixteen patients (55%) had associated hormonal secretion (cortisol secretion, n ⫽ 9; androgen secretion, n ⫽ 6; multiple secretions, n ⫽ 1). Progressive disease was demonstrated after treatment with mitotane alone (n ⫽ 2), after mitotane plus one type of cytotoxic chemotherapy (n ⫽ 19), or after mitotane plus two or more types of cytotoxic chemotherapy (n ⫽ 8), including cisplatin-based chemotherapy. In these 29 patients, mitotane levels at the time of transcatheter arterial chemoembolization were within the therapeutic range (ie, ⬎ 14 mg/L) in 17 patients, below this threshold in eight patients, and not measured in four patients. At the time of the best transcatheter arterial chemoembolization response, mitotane levels were not significantly modified compared with the level at inclusion date. No liver resection had previously been performed in any of these patients. When transcatheter arterial chemoembolization was performed, all patients received no systemic chemotherapy except mitotane. At the time of transcatheter arterial chemoembolization, 22 patients had lung metastatic lesions, five had bone metastatic lesions, and six had lymph node metastatic lesions. One patient had skin, ovarian, cerebral, and thyroid metastatic lesions. These 29 patients had a total of 103 liver metastatic lesions. Each patient had one to five liver metastases (mean, 3.6). The maximum diameter of metastatic lesions before transcatheter arterial chemoembolization ranged from 1.0 cm to 14.5 cm (mean, 3.8 cm). Fifty-four metastases measured 3 cm or less and 49 more than 3 cm in largest diameter. Tumor involvement of the liver was less than 30% in eight patients, 30%–50% in 12 patients, and more than 50% in nine patients. Chemoembolization Methods Transcatheter arterial chemoembolization of the liver was performed under local anaesthesia via a femoral access with the use of a 5-F catheter. A portogram was first obtained after injection of contrast medium into the superior mesenteric artery to assess patency of the portal trunk and intrahepatic portal
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branches. Then, a 5-F catheter was placed in the common hepatic artery to obtain an angiogram, which was used to plan the transcatheter arterial chemoembolization. A transcatheter arterial chemoembolization course comprised one injection of the drug plus embolic material. Tumors invading only one lobe or tumors invading both lobes with a tumor burden less than 30% were treated in a single session targeting one or two lobes, respectively. If tumors invaded both lobes and exhibited a tumor burden of more than 30%, two treatments targeting one lobe after the other were scheduled 1–3 months apart according to tolerance of the first chemoembolization session. For each single course of transcatheter arterial chemoembolization, the cytotoxic agent (cisplatin 1–2 mg/kg) was mixed with 10 mL of iodized oil (Lipiodol; Laboratoire Andre 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 with 1–3-mm pledgets of gelatin sponge (Hemocol; Medical Biomaterial Products, Neustadt-Glewe, Germany) until total stagnation of blood flow was achieved. Each patient received hydration (2 L per 24 h) beginning the day before chemoembolization. Antibiotics (-lactamin and clavulanate 2 g/d) and antiemetic drugs (ondansetron) were administered and hydration was maintained over a period of 2 days after the chemoembolization procedure. Evaluation Criteria The rate and duration of tumor response were defined according to Response Evaluation Criteria In Solid Tumors (RECIST) exclusively applied to liver metastases (26): a partial response was defined as a decrease of 30% or more in size of the tumor and progressive disease as an increase of 20% or more in size; otherwise the response was classified as stable (including minor response for tumor decreasing ⬍ 30%). Serial CT or magnetic resonance (MR) images were obtained with or without injection of contrast medium at 1 and 3 months and then every 3 months after each course of therapy and were used to measure tumor response. We measured the longest diameter of each metastasis and compared it versus baseline measure-
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ments for per-lesion analysis and the sum of the diameters of all metastases for the per-liver analysis. We evaluated the following as potential predictors of response: size of hepatic metastatic lesions (ⱕ 3 cm vs ⬎ 3 cm), extent of Lipiodol uptake after chemoembolization (⬍ 50% vs ⬎ 50% of surface area of metastases on first follow-up CT), and percentage of liver involvement (⬍ 30%, 30%–50%, and ⬎ 50%). Liver enzyme and creatinine levels were routinely monitored. Toxicity was assessed and graded according to the Common Terminology Criteria for Adverse Events, version 3.0 (27). No patient was lost to follow-up until disease progression or death had been documented. Statistical Methods Association was sought between morphologic response and time to progression after transcatheter arterial chemoembolization (evaluated on CT at 3 months after initial chemoembolization) and the following parameters: extent of liver involvement, tumor size, and degree of Lipiodol uptake in each metastasis. The Fisher exact test or 2 test was used for univariate analysis, and logistic regression was used for multivariate analysis. Time to progression was defined as the time between the first transcatheter arterial chemoembolization course and the progression of liver metastases (for per-liver analysis) or each metastatic lesion (for per-lesion analysis) or death. In the absence of progression, the last CT scan was considered for analysis. Extrahepatic progression was not analyzed. The incidence of progression was estimated as 1 minus the Kaplan-Meier estimate. The 95% CIs of actuarial rates were calculated with the Rothman method. Survival was defined as the time between the first chemoembolization procedure and death from any cause or the last follow-up contact for patients who were alive.
RESULTS Chemoembolization A total of 50 courses were attempted between June 1995 and August 2005 that resulted in 45 chemoembolization procedures; three patients underwent only embolization (without chemotherapy) be-
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Figure 1.
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Survival after the first course of transcatheter arterial chemoembolization.
cause of the potential risk of renal toxicity in two and previous allergy to cisplatin in one. In two cases, severe arterial spasm induced by the injection of the drug/Lipiodol emulsion during the first transcatheter arterial chemoembolization session precluded embolization. The patients received one to five courses of therapy (mean, 1.7): 16 patients had one course, eight had two courses, three had three courses, one had four courses, and one had five courses. Transcatheter arterial chemoembolization was technically successful in all cases except in two patients with arterial spasms. Morphologic Response: Progression Three months after transcatheter arterial chemoembolization, per-patient analysis showed a morphologic response in six patients (21%), stabilization in 18 (62%), and progression in the remaining five (17%). Therefore, a clinical benefit (ie, response or disease stabilization) was observed in 83% of these patients (ie, 24 of 29). In the perlesion analysis, among 103 liver metastatic lesions, 23 (22%) exhibited a partial response, 23 (22%) a minor response, 44 (43%) stabilization, and 13 (13%) progression. No delayed response (ie, “tumor improvement”) was observed after 3 months. The progression rates according to per-patient analysis were 32% (95% CI, 18%–51%) and 55% (95% CI, 34%– 74%) at 6 and 12 months, respectively. The progression rates according to perlesion analysis were 23% (95% CI, 16%– 33%) and 38% (95% CI, 27%–51%) at 6 and 12 months, respectively. Median
time to progression was 9 months (range, 1–19 months). Survival Median follow-up was 28 months. Median survival time was 11 months (range, 1.4 –31.9 months). Survival rates after the first chemoembolization session were 66% (95% CI, 47%– 80%) and 40% (95% CI, 24%–58%) at 6 and 12 months, respectively (Fig 1). The main cause of death was disease progression in 16 patients with liver (n ⫽ 8), lung (n ⫽ 4), or brain (n ⫽ 4) tumor progression. Other causes of death included sepsis (n ⫽ 2), renal insufficiency (n ⫽ 1), small bowel obstruction (n ⫽ 1), diffuse venous thrombosis (n ⫽ 1), and toxicity during subsequent systemic chemotherapy (n ⫽ 1). The cause of death was unknown in six patients: two had progressive disease on the last follow-up CT scan and four had stable disease. Four patients died during the first 3 months after chemoembolization, but none of the patients died as a consequence of the procedure. Predictors of Response At univariate analysis, a significant correlation was found between the per-lesion response to transcatheter arterial chemoembolization and the size of hepatic metastases (P ⫽ .002) and with the degree of Lipiodol uptake (P ⬍ .0001; Table). Interestingly, Lipiodol uptake was correlated with smaller tumor size (P ⫽ .0004). Indeed, 47 of 54 liver metastases smaller than 3 cm in diameter (64%) had Lipiodol up-
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Tumor Response According to Tumor Size and Lipiodol Uptake in 103 Liver Metastases Metastasis Size*
Lipiodol Uptake†
Outcome
ⱕ 3 cm
⬎ 3 cm
ⱕ 50%
⬎ 50%
Overall
Partial response Minor response Stable disease Progressive disease Overall
17/64 (31) 13/64 (24) 23/64 (43) 1/64 (2) 64
6/49 (12) 10/49 (20) 21/49 (43) 12/49 (24) 49
2/33 (6) 3/33 (9) 16/33 (48) 12/33 (36) 33
21/70 (30) 20/70 (29) 28/70 (40) 1/70 (1) 70
23 23 44 13 103
Note.—Values in parentheses are percentages. * P ⫽ .002 between groups. † P ⬍ .0001 between groups (2 test).
Figure 2.
Time to progression according to tumor size.
Figure 3.
Time to progression according to Lipiodol uptake in liver metastases.
take exceeding 50%, compared with only 25 of 49 larger than 3 cm in diameter (36%). On multivariate analysis (ie, logistic regression), response to chemoembolization remained independently associated with tumor size (⬍ 3 cm; P ⫽ .05) and Lipiodol uptake (⬎ 50%; P ⫽ .003). Shorter time to per-lesion progression
was associated with liver metastases that were larger than 3 cm and Lipiodol uptake lower than 50% (P ⫽ .008 and P ⬍ .0001, respectively; Figs 2, 3). On multivariate analysis, larger tumor size and lack of Lipiodol uptake remained significantly associated with shorter time to progression (P ⫽ .01 and P ⬍ .0001, respectively). Six- and 12-month pro-
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gression rates of metastases smaller than 3 cm were both 11% and were 37% and 74%, respectively, for metastases larger than 3 cm. Six and 12-month progression rates of metastases with Lipiodol uptake greater than 50% were 7% and 10%, respectively, and were 57% and 100%, respectively, for metastases with Lipiodol uptake lower than 50%. Toxicity After transcatheter arterial chemoembolization, 18 patients (62%) had nausea and vomiting, including 13 grade 1 episodes (45%) and five grade 2 episodes (17%) (27). Seventeen patients (59%) had abdominal pain: 10 (34%) grade 1, four (14%) grade 2, and 3 (10%) grade 3. These symptoms were controlled with antalgic drugs (eg, paracetamol or opioid derivatives). Among these 17 patients, two had symptoms that lasted 5 days, including grade 3 fever and abdominal pain, which were controlled with symptomatic treatments and antibiotics. Major postembolization tumor necrosis (ie, hypodensity of tumor and no enhancement after contrast medium injection) was demonstrated on CT in the two patients with prolonged symptoms. No significant relationship was found between fever after transcatheter arterial chemoembolization and the extent of liver involvement. However, a trend was noted because fever was observed after chemoembolization in 13% of patients with liver involvement of less than 30% (one of eight), and in 42% of patients with liver involvement exceeding 30% (nine of 21). After the procedure, grade 1, 2, or 3 liver toxicities occurred in 69% (n ⫽ 20), 24% (n ⫽ 7), and 7% (n ⫽ 2) of patients, respectively, and normalized within 4 –10 days in all patients. No renal toxicity occurred. Hospitalization lasted from 3 to 6 days (mean, 4.6 d; range, 3– 6 d) after chemoembolization. No procedure-related mortality was observed after the procedure. At the time of the best chemoembolization response, mitotane levels did not significantly change compared with levels at the inclusion date.
DISCUSSION In cases of adrenocortical carcinoma with metastases, the number of metastatic organs and the mitotic in-
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dex were recently highlighted as exerting a major prognostic impact (7). In addition, in these patients, the liver is one of the two most frequent sites of distant metastases, together with the lung, and frequently the first site involved (6 – 8). Most liver tumors— especially highly arterialized tumors, such as hepatocellular carcinoma or neuroendocrine tumors metastases— are reported to have nearly 100% of blood inflow from the hepatic artery. This preferential arterial feeding probably explains the favorable results reported with intraarterial treatment such as transcatheter arterial chemoembolization. The fact that liver metastases from adrenocortical carcinoma exhibit hypervascular patterns signified that transcatheter arterial chemoembolization could be considered as a promising antitumor tool in this group of endocrine tumors. This hypervascularized feature of adrenocortical carcinoma also supports the use of angiogenesis inhibitors in these patients. Patients with adrenocortical carcinoma with isolated or predominant liver metastases were enrolled in the present study because we consider liver progression to be a significant cause of death. This was true even in one patient with diffuse metastases, including cerebral metastases, which were stabilized with external radiation therapy. In our experience, transcatheter arterial chemoembolization demonstrated a 83% rate of tumor control, including 21% objective responses and a 62% stabilization rate in patients with adrenocortical carcinoma. More importantly, the duration of liver responses exceeded 6 and 12 months in 68% and 45% of patients, respectively, allowing them to attain an 11-month median survival time. In addition, an even higher rate of long-term tumor control was observed in patients with adrenocortical carcinoma with liver metastases smaller than 3 cm, as 89% were nonprogressive 12 months after transcatheter arterial chemoembolization, including a 31% incidence of partial response. As all patients with adrenocortical carcinoma had progressive disease at the time of study entry and no other systemic antitumor therapy but mitotane was given during chemoembolization, these preliminary results are encouraging even if they are limited to the liver. Indeed, these results compared
Cazejust et al favorably with the 4-month maximum progression-free survival time obtained with irinotecan or the 5.5-month median survival time reported with the erlotinib/gemcitabine combination in two previous third-line adrenocortical carcinoma studies (16,17). It is noteworthy that none of the patients who had a mitotane level lower than the therapeutic threshold at study initiation experienced an increase of mitotane level within the therapeutic range during study evaluation. Of course, only a future randomized study combining, for instance, systemic chemotherapy with or without liver transcatheter arterial chemoembolization will definitely determine the place of this new tool in the therapeutic arsenal against adrenocortical carcinoma. Metastases from adrenocortical carcinoma smaller than 3 cm had a higher Lipiodol uptake and exhibited a better objective response rate (P ⬍ .0001). A trend was also found between the percentage of liver involvement and partial response, as five of six patients who showed a partial response had liver involvement of less than 50%; this was also reported by our group in neuroendocrine tumors (28). Taken together, these results prompt us to propose transcatheter arterial chemoembolization early in the course of the disease, as soon as liver metastases are detected. The aggressiveness of most adrenocortical carcinoma in contrast with well differentiated neuroendocrine carcinoma also supports this proposal. In addition, our results suggest that the percentage of Lipiodol uptake may help predict liver metastases likely to respond to this therapeutic option. Postembolic syndrome, including transient abdominal pain, fever, nausea, and liver enzyme elevation, was frequently observed after transcatheter arterial chemoembolization (38 of 50 courses; 76%), and was below grade 2 in the majority of patients. In four patients (five of 50 courses), severe postembolization syndrome occurred. Fever occurred more frequently when tumors were large, probably because of a larger volume of induced tumor necrosis (trend, P ⫽ .20, Fisher test). Two of the four patients who had severe postembolization syndrome with fever and abdominal pain for 7 days had substantial tumor necrosis on CT. The other two had severe postembolization syndrome 2 and 4 days, respec-
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tively, so no CT scan was obtained for these patients. This also argues in favor of early treatment when the tumor volume is small. Otherwise, in patients with extensive disease, the liver should be treated in several sessions to decrease toxicity. We used chemoembolization with cisplatin, a Lipiodol emulsion, and gelatin sponge pledgets in 90% of the procedures because chemoembolization was demonstrated to be superior to chemotherapy with Lipiodol or embolization alone in hepatocellular carcinoma (22,29). The same holds true for liver metastases from islet cell tumors; adding intraarterial chemotherapy to hepatic arterial embolization improves outcome, with response rates of 50% and 25% for transcatheter arterial chemoembolization and embolization alone, respectively (24). New embolic agents loaded with drugs that have recently been used successfully in hepatocellular carcinoma (30) or neuroendocrine tumors (31) might further improve treatment efficacy and lower the risk of systemic side effects. Indeed, pharmacokinetic studies in animals (32) and humans (30) have demonstrated a 10-fold reduction of systemic peak drug concentration when such drug-eluting beads were compared with conventional intraarterial chemoembolization with a drug/ Lipiodol mixture and gelatin sponge pledgets (30,32), as applied in this study, suggesting that drug was more concentrated in the liver (and therefore in the liver metastases). However, only one of these studies was randomized (26), making the interest of combining cytotoxic chemotherapy with embolization still a matter of discussion. Therefore, whether such loadable embolic material may further improve the efficacy of intraarterial treatments in the future remains to be demonstrated. To date, platinum-derived drugs, the most efficient systemic drugs in adrenocortical carcinoma, cannot be loaded efficiently, and doxorubicin or irinotecan are the only loadable products. However, the role of doxorubicin or irinotecan as effective antitumor agents in adrenocortical carcinoma respectively continues to be challenged (33) or is considered poor (15). The major limitations of the present study are the small size and the heterogeneity of the study group. The limited size is related to the extreme rarity
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of the disease. The heterogeneity is a result of the use of transcatheter arterial chemoembolization at different times after the diagnosis of liver metastases, often after two or three lines of systemic chemotherapy. The first patients in our series received transcatheter arterial chemoembolization for advanced liver disease (before 2000), but more recently (since 2000), we performed transcatheter arterial chemoembolization earlier during the course of liver metastases. Cumulative response was observed in 83% patients at 3 months after chemoembolization, with a median time to progression of 9 months, indicated that transcatheter arterial chemoembolization is a new tool to be included in the therapeutic arsenal to treat adrenocortical carcinoma. Early treatment when liver metastases are smaller than 3 cm should be preferred. References 1. Gicquel C, Baudin E, Lebouc Y, Schlumberger M. Adrenocortical carcinoma. Ann Oncol 1997; 8:423– 427. 2. Allolio B, Fassnacht M. Adrenocortical carcinoma: clinical update. J Clin Endocrinol Metab 2006; 91:2027–2037. 3. Weiss LM. Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors. Am J Surg Pathol 1984; 8:163–169. 4. Weiss LM, Medeiros LJ, Vickery AL Jr. Pathologic features of prognostic significance in adrenocortical carcinoma. Am J Surg Pathol 1989; 13:202–206. 5. Gicquel C, Bertagna X, Gaston V, et al. Molecular markers and long-term recurrences in a large cohort of patients with sporadic adrenocortical tumors. Cancer Res 2001; 61:6762–2767. 6. Abiven G, Coste J, Groussin L, et al. Clinical and biological features in the prognosis of adrenocortical cancer: poor outcome of cortisol-secreting tumors in a series of 202 consecutive patients. J Clin Endocrinol Metab 2006; 91:2650 –2655. 7. Assie G, Antoni G, Tissier F, et al. Prognostic parameters of metastatic adrenocortical carcinoma. J Clin Endocrinol Metab 2007; 92:148 –154. 8. Berruti A, Terzolo M, Sperone P, et al. Etoposide, doxorubicin and cisplatin plus mitotane in the treatment of advanced adrenocortical carcinoma: a large prospective phase II trial. Endocr Relat Cancer 2005; 12:657– 666. 9. Ahlman H, Jansson S, Wangberg B, et al. Adrenocortical carcinoma– diagnostic and therapeutical implications. Eur J Surg 1993; 159:149 –158.
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