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 carci- noma 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 involve- ment, 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 = 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 = . 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 Desmou- lins, 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: debaere@igr.fr
None of the authors have identified a conflict of interest.
C 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 adreno- lytic agents such as cisplatin or mito- tane 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 concern- ing new topoisomerase type 1 or epi- dermal growth factor receptor inhibi- tors combined with gemcitabine have recently demonstrated very limited antitumor activity (15-17). More re- cently, the preliminary results of mo- lecular targeting of insulin-like growth factor 1 receptor have been published and appear promising (18-20). How- ever, reports of complete response in metastatic adrenocortical carcinoma are still lacking. Along with efforts to develop new therapeutic strategies, well known techniques such as chemoembo- lization could be studied in adrenocor-
tical carcinoma, possibly in combination with other well known treatments such as mitotane while awaiting more effec- tive 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 arte- rial chemoembolization has been dem- onstrated to achieve significant antitu- mor activity in several cancers. Indeed, transcatheter arterial chemo- embolization is widely used for the treatment of hepatocellular carcinoma (22) and liver metastases from neu- roendocrine 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 hor- mone secretions.
We undertook a single-center retro- spective study to obtain insights into the tolerance and efficacy of transcath- eter arterial chemoembolization in pa- tients with progressive liver metasta- ses from adrenocortical carcinoma. In addition, we investigated predictors of response to transcatheter arterial che- moembolization.
MATERIALS AND METHODS
Inclusion Criteria and Patient Characteristics
Ninety-one consecutive patients with metastatic adrenocortical carci- noma were treated in a single institu- tion between 1995 and 2005. Data con- cerning 29 consecutive patients (23 women and six men; median age, 41 years; age range, 15-71 y) with pro- gressive liver metastases from adreno- cortical carcinoma treated with trans- catheter arterial chemoembolization from June 1995 to August 2005 were retrospectively reviewed. The other 62 patients were not treated with trans- catheter arterial chemoembolization because liver involvement was not considered to represent the predomi- nant 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 chemoemboliza- tion in our center was progression of liver metastases documented by two
consecutive abdominal computed to- mography (CT) scans in patients with isolated or predominant liver metasta- ses. Sixteen patients (55%) had associ- ated hormonal secretion (cortisol se- cretion, n = 9; androgen secretion, n = 6; multiple secretions, n = 1). Progres- sive disease was demonstrated after treatment with mitotane alone (n = 2), after mitotane plus one type of cyto- toxic chemotherapy (n = 19), or after mitotane plus two or more types of cytotoxic chemotherapy (n = 8), in- cluding cisplatin-based chemother- apy. In these 29 patients, mitotane lev- els 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 chemoem- bolization response, mitotane levels were not significantly modified com- pared with the level at inclusion date. No liver resection had previously been performed in any of these patients. When transcatheter arterial chemoem- bolization 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 thy- roid metastatic lesions. These 29 pa- tients had a total of 103 liver metastatic lesions. Each patient had one to five liver metastases (mean, 3.6). The max- imum diameter of metastatic lesions before transcatheter arterial chemoem- bolization ranged from 1.0 cm to 14.5 cm (mean, 3.8 cm). Fifty-four metasta- ses 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 chemoembo- lization of the liver was performed un- der local anaesthesia via a femoral ac- cess with the use of a 5-F catheter. A portogram was first obtained after injec- tion of contrast medium into the superior mesenteric artery to assess patency of the portal trunk and intrahepatic portal
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 chemoem- bolization course comprised one injec- tion of the drug plus embolic material. Tumors invading only one lobe or tu- mors invading both lobes with a tu- mor burden less than 30% were treated in a single session targeting one or two lobes, respectively. If tu- mors invaded both lobes and exhib- ited 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; Labora- toire Andre Guerbet, Aulnay sous Bois, France) through a three-way stopcock to obtain a water-in-oil emulsion. After in- jection of the emulsion, if the targeted artery was still patent, embolization was performed with 1-3-mm pledgets of gelatin sponge (Hemocol; Medical Bio- material Products, Neustadt-Glewe, Germany) until total stagnation of blood flow was achieved. Each patient re- ceived hydration (2 L per 24 h) begin- ning the day before chemoembolization. Antibiotics (ß-lactamin and clavulanate 2 g/d) and antiemetic drugs (ondanse- tron) were administered and hydration was maintained over a period of 2 days after the chemoembolization procedure.
Evaluation Criteria
The rate and duration of tumor re- sponse were defined according to Re- sponse Evaluation Criteria In Solid Tumors (RECIST) exclusively applied to liver metastases (26): a partial re- sponse 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 re- sponse was classified as stable (includ- ing minor response for tumor decreas- ing < 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 tu- mor response. We measured the long- est diameter of each metastasis and compared it versus baseline measure-
ments for per-lesion analysis and the sum of the diameters of all metastases for the per-liver analysis. We evalu- ated the following as potential predic- tors of response: size of hepatic meta- static lesions (≤ 3 cm vs > 3 cm), extent of Lipiodol uptake after chemo- embolization (< 50% vs > 50% of sur- face area of metastases on first fol- low-up CT), and percentage of liver involvement (< 30%, 30%-50%, and > 50%). Liver enzyme and creatinine levels were routinely monitored. Tox- icity was assessed and graded accord- ing to the Common Terminology Cri- teria 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 chemoemboli- zation) and the following parameters: extent of liver involvement, tumor size, and degree of Lipiodol uptake in each metastasis. The Fisher exact test or X test was used for univariate anal- ysis, and logistic regression was used for multivariate analysis. Time to pro- gression was defined as the time be- tween 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 progres- sion 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 chemoembo- lization procedure and death from any cause or the last follow-up contact for pa- tients who were alive.
RESULTS
Chemoembolization
A total of 50 courses were attempted between June 1995 and August 2005 that resulted in 45 chemoembolization proce- dures; three patients underwent only em- bolization (without chemotherapy) be-
1.00
0.90
0.80
0.70
0.60
0.50
0.40
0.30
0.20
0.10
0.00
0
3
6
9
12
15
18
21
24
27
30
33
36
Time (months)
Number of patients
29
25
19
15
11
7
6
5
4
2
2
1
1
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 chemo- embolization session precluded embo- lization. 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 chemo- embolization was technically success- ful in all cases except in two patients with arterial spasms.
Morphologic Response: Progression
Three months after transcatheter ar- terial chemoembolization, per-patient analysis showed a morphologic re- sponse in six patients (21%), stabiliza- tion 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 per- lesion analysis, among 103 liver meta- static lesions, 23 (22%) exhibited a par- tial response, 23 (22%) a minor response, 44 (43%) stabilization, and 13 (13%) progression. No delayed re- sponse (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 per- lesion 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 dis- ease 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 ve- nous thrombosis (n = 1), and toxicity during subsequent systemic chemo- therapy (n = 1). The cause of death was unknown in six patients: two had progressive disease on the last fol- low-up CT scan and four had stable disease. Four patients died during the first 3 months after chemoemboliza- tion, 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 up- take (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-
Tumor Response According to Tumor Size and Lipiodol Uptake in 103 Liver Metastases
| Outcome | Metastasis Size* | Lipiodol Uptaket | Overall | ||
|---|---|---|---|---|---|
| ≤ 3 cm | > 3 cm | ≤ 50% | > 50% | ||
| Partial response | 17/64 (31) | 6/49 (12) | 2/33 (6) | 21/70 (30) | 23 |
| Minor response | 13/64 (24) | 10/49 (20) | 3/33 (9) | 20/70 (29) | 23 |
| Stable disease | 23/64 (43) | 21/49 (43) | 16/33 (48) | 28/70 (40) | 44 |
| Progressive disease | 1/64 (2) | 12/49 (24) | 12/33 (36) | 1/70 (1) | 13 |
| Overall | 64 | 49 | 33 | 70 | 103 |
Note .- Values in parentheses are percentages.
* P = . 002 between groups.
+ P < . 0001 between groups (x2 test).
Progression according to tumor size
1.00
0.90
0.80
0.70
0.60
0.50
0.40
-⇐ 3 cm
0.30
+>3 cm
0.20
logrank p < 0.0001
0.10
0.00
0
3
6
9
12
15
Time (months)
Progression according to lipiodol uptake
1.00
0.90
0.80
0.70
0.60
+ Uptake < 50%
0.50
- Uptake > 50%
0.40
logrank p < 0.0001
0.30
0.20
0.10
0.00
0
3
6
9
12
15
Time (months)
take exceeding 50%, compared with only 25 of 49 larger than 3 cm in di- ameter (36%). On multivariate analy- sis (ie, logistic regression), response to chemoembolization remained inde- pendently 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 up- take lower than 50% (P = . 008 and P < .0001, respectively; Figs 2, 3). On multi- variate analysis, larger tumor size and lack of Lipiodol uptake remained sig- nificantly associated with shorter time to progression (P = . 01 and P < . 0001, respectively). Six- and 12-month pro-
gression rates of metastases smaller than 3 cm were both 11% and were 37% and 74%, respectively, for metas- tases larger than 3 cm. Six and 12-month progression rates of metastases with Lipi- odol uptake greater than 50% were 7% and 10%, respectively, and were 57% and 100%, respectively, for metastases with Li- piodol uptake lower than 50%.
Toxicity
After transcatheter arterial chemo- embolization, 18 patients (62%) had nausea and vomiting, including 13 grade 1 episodes (45%) and five grade 2 episodes (17%) (27). Seventeen pa- tients (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, includ- ing grade 3 fever and abdominal pain, which were controlled with symptom- atic treatments and antibiotics. Major postembolization tumor necrosis (ie, hypodensity of tumor and no en- hancement after contrast medium in- jection) was demonstrated on CT in the two patients with prolonged symptoms. No significant relationship was found between fever after trans- catheter arterial chemoembolization and the extent of liver involvement. However, a trend was noted because fever was observed after chemoembo- lization 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 normal- ized within 4-10 days in all patients. No renal toxicity occurred. Hospital- ization lasted from 3 to 6 days (mean, 4.6 d; range, 3-6 d) after chemoembo- lization. No procedure-related mortal- ity was observed after the procedure. At the time of the best chemoemboli- zation response, mitotane levels did not significantly change compared with levels at the inclusion date.
DISCUSSION
In cases of adrenocortical carci- noma with metastases, the number of metastatic organs and the mitotic in-
dex were recently highlighted as exert- ing 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 in- volved (6-8). Most liver tumors-es- pecially 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 prob- ably explains the favorable results re- ported with intraarterial treatment such as transcatheter arterial chemo- embolization. The fact that liver me- tastases from adrenocortical carci- noma exhibit hypervascular patterns signified that transcatheter arterial chemoembolization could be consid- ered as a promising antitumor tool in this group of endocrine tumors. This hypervascularized feature of adreno- cortical carcinoma also supports the use of angiogenesis inhibitors in these patients. Patients with adrenocortical carcinoma with isolated or predomi- nant 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 demon- strated 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 re- sponses 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 me- tastases smaller than 3 cm, as 89% were nonprogressive 12 months after trans- catheter arterial chemoembolization, in- cluding a 31% incidence of partial response. As all patients with adre- nocortical carcinoma had progressive disease at the time of study entry and no other systemic antitumor therapy but mitotane was given during chemoem- bolization, these preliminary results are encouraging even if they are limited to the liver. Indeed, these results compared
favorably with the 4-month maximum progression-free survival time ob- tained 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 note- worthy that none of the patients who had a mitotane level lower than the therapeutic threshold at study initia- tion experienced an increase of mito- tane level within the therapeutic range during study evaluation. Of course, only a future randomized study com- bining, for instance, systemic chemo- therapy with or without liver trans- catheter arterial chemoembolization will definitely determine the place of this new tool in the therapeutic arsenal against adrenocortical carcinoma.
Metastases from adrenocortical car- cinoma 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 per- centage of liver involvement and par- tial 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 to- gether, these results prompt us to pro- pose transcatheter arterial chemoem- bolization 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 per- centage of Lipiodol uptake may help pre- dict liver metastases likely to respond to this therapeutic option.
Postembolic syndrome, including transient abdominal pain, fever, nau- sea, and liver enzyme elevation, was frequently observed after transcathe- ter 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 se- vere postembolization syndrome with fever and abdominal pain for 7 days had substantial tumor necrosis on CT. The other two had severe postemboli- zation syndrome 2 and 4 days, respec-
tively, so no CT scan was obtained for these patients. This also argues in fa- vor of early treatment when the tumor volume is small. Otherwise, in pa- tients 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 chemoemboliza- tion was demonstrated to be superior to chemotherapy with Lipiodol or em- bolization alone in hepatocellular car- cinoma (22,29). The same holds true for liver metastases from islet cell tu- mors; adding intraarterial chemother- apy to hepatic arterial embolization improves outcome, with response rates of 50% and 25% for transcatheter arterial chemoembolization and embo- lization alone, respectively (24). New embolic agents loaded with drugs that have recently been used successfully in hepatocellular carcinoma (30) or neuroendocrine tumors (31) might fur- ther 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 intraarte- rial 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 there- fore in the liver metastases). However, only one of these studies was random- ized (26), making the interest of com- bining cytotoxic chemotherapy with embolization still a matter of discus- sion. Therefore, whether such loadable embolic material may further improve the efficacy of intraarterial treatments in the future remains to be demon- strated. To date, platinum-derived drugs, the most efficient systemic drugs in adrenocortical carcinoma, cannot be loaded efficiently, and doxo- rubicin or irinotecan are the only load- able products. However, the role of doxorubicin or irinotecan as effective an- titumor agents in adrenocortical carci- noma respectively continues to be chal- lenged (33) or is considered poor (15).
The major limitations of the present study are the small size and the heter- ogeneity of the study group. The lim- ited size is related to the extreme rarity
of the disease. The heterogeneity is a result of the use of transcatheter arte- rial chemoembolization at different times after the diagnosis of liver me- tastases, often after two or three lines of systemic chemotherapy. The first patients in our series received trans- catheter 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 che- moembolization, with a median time to progression of 9 months, indicated that transcatheter arterial chemoembo- lization is a new tool to be included in the therapeutic arsenal to treat adreno- cortical 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 car- cinoma. Ann Oncol 1997; 8:423-427.
2. Allolio B, Fassnacht M. Adreno- cortical carcinoma: clinical update. J Clin Endocrinol Metab 2006; 91:2027-2037.
3. Weiss LM. Comparative histologic study of 43 metastasizing and nonme- tastasizing adrenocortical tumors. Am J Surg Pathol 1984; 8:163-169.
4. Weiss LM, Medeiros LJ, Vickery AL Jr. Pathologic features of prognostic sig- nificance 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 re- currences 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 tu- mors in a series of 202 consecutive pa- tients. 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 Endo- crinol Metab 2007; 92:148-154.
8. Berruti A, Terzolo M, Sperone P, et al. Etoposide, doxorubicin and cisplatin plus mitotane in the treatment of ad- vanced 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-diag- nostic 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 confer- ence. Endocr Relat Cancer 2005; 12: 667-680.
11. Wooten MD, King DK. Adrenal cor- tical 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-di- chlorodiphenildichloroethane (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 adreno- cortical carcinoma with mitotane: re- sults in a consecutive series of 96 pa- tients. Br J Cancer 1994; 69:947-951.
14. Olaussen KA, Dunant A, Fouret P, et al. DNA repair by ERCC1 in non- small-cell lung cancer and cisplatin- based 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 (iri- notecan, CPT-11) in metastatic adreno- cortical carcinoma. Ann Oncol 2002; 13: 1806-1809.
16. Kirschner LS. Emerging treatment strategies for adrenocortical carcino- ma: a new hope. J Clin Endocrinol Metab 2006; 91:14-21.
17. Quinkler M, Hahner S, Wortmann S, et al. Treatment of advanced adrenocor- tical 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 pharmacoki- netics 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 contin- uous 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 carci- noma. CA Cancer J Clin 1987; 37:348- 365.
22. Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoem-
bolization improves survival. Hepato- logy 2003; 37:429-442.
23. Eriksson BK, Larsson EG, Skogseid BM, Lofberg AM, Lorelius LE, Oberg KE. Liver embolizations of patients with malignant neuroendocrine gastro- intestinal tumors. Cancer 1998; 83: 2293-2301.
24. Gupta S, Johnson MM, Murthy R, et al. Hepatic arterial embolization and che- moembolization for the treatment of patients with metastatic neuroendo- crine tumors: variables affecting re- sponse rates and survival. Cancer 2005; 104:1590-1602.
25. Roche A, Girish BV, de Baere T, et al. Trans-catheter arterial chemoemboliza- tion as first-line treatment for hepatic metastases from endocrine tumors. Eur Radiol 2003; 13:136-140.
26. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92:205-216.
27. Trotti A, Colevas AD, Setser A, et al. CTCAE v3.0: development of a com- prehensive grading system for the ad- verse effects of cancer treatment. Semin Radiat Oncol 2003; 13:176-181.
28. Roche A, Girish BV, de Baere T, et al. Prognostic factors for chemoemboliza- tion in liver metastasis from endocrine tumors. Hepatogastroenterology 2004; 51:1751-1756.
29. Lo CM, Ngan H, Tso WK, et al. Randomized controlled trial of transar- terial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 2002; 35:1164-1171.
30. Varela M, Real MI, Burrel M, et al. Chemoembolization of hepatocellular carcinoma with drug eluting beads: effi- cacy and doxorubicin pharmacokinetics. J Hepatol 2007; 46:474-481.
31. Coenegrachts K, de Baère T, Abdel Re- him M, Lafont C, Dromain C, Hakime A. Transarterial chemoembolization (TACE) of neuroendocrine hepatic me- tastases using drug eluting beads. Pre- sented at the 91st Scientific Assembly of the Radiological Society of North America; November 27 to December 2, 2005; Chicago, IL.
32. Hong K, Khwaja A, Liapi E, Torbenson MS, Georgiades CS, Geschwind JF. New intra-arterial drug delivery sys- tem for the treatment of liver cancer: preclinical assessment in a rabbit model of liver cancer. Clin Cancer Res 2006; 12:2563-2567.
33. Decker RA, Kuehner ME. Adreno- cortical carcinoma. Am Surg 1991; 57: 502-513.