Bevacizumab plus capecitabine as a salvage therapy in advanced adrenocortical carcinoma

in European Journal of Endocrinology
View More View Less
  • 1 Endocrine and Diabetes Unit, Clinical Endocrinology, Department of Radiology, Department of Internal Medicine I, University Hospital of Würzburg, University of Würzburg, Oberdürrbacher Strasse 6, 97080 Würzburg, Germany

Objective

No standard therapy for advanced adrenocortical carcinoma (ACC) is established by any randomized trial but a consensus conference 2003 recommended mitotane as monotherapy or combined with etoposide, doxorubicin and cisplatin or with streptozotocin as first-line systemic therapy. However, there is no evidence for any therapy beneficial in patients failing these therapies. Therefore, we evaluated the effects of the anti-VEGF antibody bevacizumab plus capecitabine as salvage therapy in ACC.

Methods

Patients registered with the German ACC Registry with refractory ACC progressing after cytotoxic therapies were offered treatment with bevacizumab (5 mg/kg body weight i.v. every 21 days) and oral capecitabine (950 mg/m2 twice daily for 14 days followed by 7 days of rest) in 2006–2008. Evaluation of tumour response was performed by imaging according to response evaluation criteria in solid tumours every 12 weeks.

Results

Ten patients were treated with bevacizumab plus capecitabine. None of them experienced any objective response or stable disease. Two patients had to stop therapy after few weeks due to hand-foot syndrome, and three patients died on progressive disease within 12 weeks. Other adverse events were mild (grade I–II). Median survival after treatment initiation was 124 days.

Conclusions

Bevacizumab plus capecitabine has no activity in patients with very advanced ACC. Hence, this regimen cannot be recommended as a salvage therapy.

Abstract

Objective

No standard therapy for advanced adrenocortical carcinoma (ACC) is established by any randomized trial but a consensus conference 2003 recommended mitotane as monotherapy or combined with etoposide, doxorubicin and cisplatin or with streptozotocin as first-line systemic therapy. However, there is no evidence for any therapy beneficial in patients failing these therapies. Therefore, we evaluated the effects of the anti-VEGF antibody bevacizumab plus capecitabine as salvage therapy in ACC.

Methods

Patients registered with the German ACC Registry with refractory ACC progressing after cytotoxic therapies were offered treatment with bevacizumab (5 mg/kg body weight i.v. every 21 days) and oral capecitabine (950 mg/m2 twice daily for 14 days followed by 7 days of rest) in 2006–2008. Evaluation of tumour response was performed by imaging according to response evaluation criteria in solid tumours every 12 weeks.

Results

Ten patients were treated with bevacizumab plus capecitabine. None of them experienced any objective response or stable disease. Two patients had to stop therapy after few weeks due to hand-foot syndrome, and three patients died on progressive disease within 12 weeks. Other adverse events were mild (grade I–II). Median survival after treatment initiation was 124 days.

Conclusions

Bevacizumab plus capecitabine has no activity in patients with very advanced ACC. Hence, this regimen cannot be recommended as a salvage therapy.

Introduction

Owing to the rarity of adrenocortical carcinoma (ACC), there is no treatment established by any randomized trial (1). Surgery is regarded as therapy of choice in all patients with resectable tumour, but 25% of patients already have distant metastases at the time of primary diagnosis and the majority of patients develop metastases even after assumed curative surgery (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12). In 2003, an international consensus conference on the management of ACC recommended for patients with advanced metastatic disease mitotane as monotherapy or combined with etoposide, doxorubicin and cisplatin (13) or with streptozotocin (14) as first-line systemic treatment based on two phase II trials leading to an evidence level not better than 2 (1). The two latter regimens are currently compared in the first randomized trial in this disease (FIRM-ACT trial, www.firm-act.org). Up to now, more than 280 patients have been enrolled, but results will not be available before 2011 after analysis of 300 patients. Regarding second-line therapies, the consensus conference acknowledged that only anecdotal evidence is available and recommended to use the aforementioned regimens that were not used as first-line. For patients failing these treatment regimens, no recommendations could be given and it is obvious that new treatment options are needed.

The initiation of the FIRM-ACT trial has led to a profound change in the care of patients with ACC in Germany (15). Since 2004, an increasing number of patients with ACC consult few specialized centres regarding treatment options. However, as expected from previous experience with cytotoxic chemotherapy, many patients fail both FIRM-ACT protocols or progress after initial response leading to an urgent demand for salvage therapy in these often young patients. The FIRM-ACT investigators in Germany (organized in the German Adrenal Network Improving Treatment and Medical Eduction (GANIMED) network) responded to this growing need by developing several defined salvage protocols for compassionate use in this patient group. These protocols were offered to clinicians caring for patients with progressive ACC registered in the German ACC Registry (www.nebennierenkarzinom.de; Clinicaltrials.gov identifier: NCT00453674) allowing local investigators and the patient to choose between different options and to prospectively evaluate the response to therapy with the aim to identify new active treatment protocols. The aim of this standardization of therapeutic efforts in all GANIMED centres was to provide some evidence for potentially valuable treatment regimens in a relatively short period of time. These protocols were influenced by preclinical data concerning, e.g. receptor expression, theoretical considerations on tumorigenesis and promising advances in other carcinoma entities with limited prognosis.

Anti-angiogenic substances have been discussed in several reviews as an interesting option for advanced ACC (16, 17, 18). Although none of the clinically approved drugs have been tested in preclinical or clinical studies in ACC, there was some evidence that an anti-angiogenic approach might be of benefit for patients with ACC. The majority of more than 160 investigated ACC tumour samples showed specific staining against vascular endothelial growth factor (VEGF) and its most important receptor (VEGF receptor 2) in immunohistochemical analysis (unpublished data). Furthermore, elevated VEGF levels were reported in tumour samples and in serum of patients with ACC (19, 20). In addition, encouraging results in advanced colorectal (21), breast (22), lung (23) and renal (24) cancer were recently published showing significant prolongation of survival and good tolerance of bevacizumab, a monoclonal anti-VEGF antibody. Therefore, we adapted protocols of these entities for patients with advanced ACC. To enforce the power of the therapy regime, we combined bevacizumab with capecitabine, a prodrug of fluorouracil. Fluorouracil has been reported to have adrenolytic power on adrenal cancer cell lines (25). Whereas fluorouracil has to be given i.v., capecitabine has the charm of oral administration. In addition, trials in metastatic colorectal cancer have shown that capecitabine plus oxaliplatin (XELOX) is not inferior to standard fluorouracil plus oxaliplatin (26), and that bevacizumab in combination with XELOX significantly improved progression-free survival (27).

Here, we report on the treatment with bevacizumab and capecitabine on a compassionate use basis in ten patients with advanced ACC refractory to several cytotoxic chemotherapies.

Materials and methods

Patients

Between January 2006 and June 2008, physicians of the GANIMED network offered patients with advanced ACC treatment with bevacizumab and capecitabine when they fulfilled the following inclusion criteria: histologically proven ACC in an unresectable, locally advanced, recurrent or metastatic stage after progression despite treatment with mitotane and at least two cytotoxic chemotherapies including etoposide, doxorubicin, cisplatin and streptozotocin. All patients had radiologically measurable target lesions as defined by response evaluation criteria in solid tumours (RECIST) criteria (28), were aged over 18 years, in acceptable clinical condition (Eastern Cooperative Oncology Group stage of 0–2) including adequate haematological, renal and hepatic function, and desired further treatment. Exclusion criteria were prior exposure to anti-VEGF antibody or capecitabine/fluorouracil, other malignancies within the last 5 years, or active infections. All patients were informed of the experimental nature of the treatment and signed informed consent.

Treatment protocol

Bevacizumab (Avastin, F Hoffmann-La Roche) was given intravenously every 3 weeks in a dosage of 5 mg/kg body weight as an infusion. Capecitabine (Xeloda, F Hoffmann-La Roche) was administered orally 950 mg/m2 twice daily for 14 days followed by 7 days of rest. Dose of capecitabine was increased to 1250 mg/m2 in case of good tolerance. In general, the therapy was carried out on an outpatient basis. Continuation of concomitant administration of mitotane was permitted in patients in whom some clinical benefit was assumed despite progression during prior mitotane treatment (e.g. in patients with Cushing's syndrome).

Evaluation

Baseline evaluations included a documentation of patient history, physical examination, and performance status. A complete blood cell count, serum chemistry profile (Na, K, Ca, PO4, creatinine, glucose, aspartate aminotransferase (AST)/serum glutamate oxalacetate transaminase (SGOT), alanine aminotransferase (ALT)/serum glutamate pyruvate transaminase (SGPT), alkaline phosphatase, total bilirubin, albumin), and chest and abdominal computed tomography (CT) or magnetic resonance imaging scans were performed. This evaluation was repeated every 12 weeks, and tumour response was determined. Response was assessed using the RECIST (28). All radiological images were reviewed by the local radiologists and an independent radiologist who finally determined response. In case of progressive disease, it was recommended to stop treatment.

Drug-related adverse events and toxicities were recorded, according to the Common Toxicity Criteria of the National Cancer Institute (version 3.0).

Results

Patient characteristics

Ten patients (7 male and 3 female) with advanced ACC were treated with bevacizumab and capecitabine between May 2006 and June 2008. Patient's characteristics including initial tumour stage, hormonal activity and previous surgical, radiological or medicinal therapies are given in Table 1. Median age was 46 years, and median time from diagnosis of distant metastases to start of therapy with bevacizumab plus capecitabine was 19 months. Most patients had a history of several surgeries, and all were heavily pretreated with systemic therapies. Median number of administered drug regimens was 4 (range 3–5; Table 1). Etoposide, doxorubicin and cisplatin plus mitotane as well as streptozotocin plus mitotane were administered in all patients (nine of them within the FIRM-ACT trial). Furthermore, six patients were pretreated with gemcitabine plus erlotinib (29), three with sunitinib and three with radiotherapy and chemoembolization necessary. Five patients had concomitant mitotane, because it was at the discretion of the local physician to continue with mitotane when some clinical benefit was presumed. In two patients, endogenous glucocorticoid excess was treated with metyrapone (n=1) and RU486 (n=1) respectively.

Table 1

Patient characteristics and previous therapies.

Patient no.SexAge (years)Hormonal activityTime from diagnosis of ACC to start of BC (months)Time from diagnosis of metastasis to start of BC (months)Number of previous surgeriesPrior systemic therapies (months)Other prior therapies
1Male46N20201M (5), EDP-M (8), Sz-M (2), EG-M (3)
2Male38A19124Sz-M (2), EDP-M (5), EG (3)
3Male45N18181M (5), Th-M (4), EDP-M (4), Sz-M (4), EG-M (2)RT skull
4Male45N20202Sz-M (4), EDP-M (2), EG-M (1)
5Male50N16121M (3), EDP-M (4), Sz-M (2), EG-M (3)
6Female73A32321M (2), Sz-M (6), EDP-M (10), EG-M (8), Su (3)
7Male62N22111M (11), EDP-M (4), Sz-M (2)
8Female46C22224M (4), Sz-M (8), M (3), EDP-M (2), Su-M (3), CE liver, RT spin
9Male68C42154M (4), Sz-M (2), EDP-M (3),
10Female42A,C48272M (1), EDP-M (5), Sz-M (3), EDC-M (3), Su-M (3)RT lymph node

N, hormonally inactive or with no initial hormonal work-up; A, androgen excess; C, cortisol excess. BC, bevacizumab and capecitabine. Duration of prior systemic therapies is given in months in parentheses; M, mitotane mono; EDP-M, etoposide, doxorubicin, cisplatin, mitotane; EDC-M, etoposide, doxorubicin, carboplatin, mitotane; Sz-M, streptozotocin and mitotane; EG, erlotinib and gemcitabine; EG-M, erlotinib, gemcitabine, mitotane; Th-M, thalidomide, mitotane; Su-M, sunitinib, mitotane; Su, sunitinib; RT, radiotherapy; CE, chemoembolization.

All patients had significant tumour burden with a median sum of longest diameter of the pre-specified target lesions of 205 mm (range 93–501 mm), and progressing disease was documented before initiation of bevacizumab plus capecitabine. Six patients had local recurrence, and all suffered from tumour manifestations in at least two different organs as shown in Table 2.

Table 2

Disease status and results of evaluation.

Sum (in mm)of the longest diameter (number of target lesions)
Patient no.Sites of tumour manifestationsVEGF expressionConcomitant mitotane (maximum plasma level mg/l)Cumulative dose of C (g)Cycles of BBaseline1st stagingNumber of new mets (1st staging)Overall, responseTreatment after BCSurvival since start BC (months)
1lr, ab, li, lu, hiNA12.7112197 (3)125 (3)3 luPDvac3
2lr, lu, mu, ab, axNANo3086129 (3)132 (3)2 ab, liPDsu9
3lr, li, lu, bo, ab+9.02343378 (10)aPD2
4ab, lu, muNA10.6561200 (6)306 (6)1 liPDvac4
5lr, ab, li, lu+17.01121462 (10)aPD1
6ab, lu, li, hi+No1684197 (10)318 (10)PD5
7li, lu+13.4237493 (7)232 (7)2 liPDsu4
8bo, lu, li, muNANob1123385 (10)aPD2
9lr, ab, li, lu, hiNANo1122209 (10)266 (10)PDRIT, th31
10lr, li, hi, scNANoc1684501 (10)480 (10)PDdRT, RCT6

B, bevacizumab; C, capecitabine. Mets, metastases. Site of tumour manifestation: lr, local recurrence; li, liver; lu, lung; bo, bone; ab, abdominal; mu, muscular lesion; ax, axillar lesion; sc, supraclavicular lesion; hi, hilar lesion. NA, not available; +, positive VEGF staining. PD, progressive disease. su, sunitinib; vac, vaccination with survivin peptide; RIT, radioiodine therapy with iodmetomidate; th, thalidomide; RT, radiotherapy; RCT, rosiglitazone, celecoxib and trofosphamide.

Patient died before first control staging.

Concomitant RU486.

Concomitant metyrapone.

Despite stable target lesions the need for an emergency radiation therapy due to superior vena cava syndrome led to the diagnosis of PD.

In all four patients, in whom tumour samples were stained with anti-VEGF antibody, expression of VEGF protein was detectable in the tumour cells.

Outcome

None of the ten patients experienced any objective response or stable disease during therapy with bevacizumab plus capecitabine. Three of them had already died due to progressive disease before first scheduled restaging at 12 weeks. Two patients (nos 1 and 4) experienced relevant hand-foot syndrome and had to stop therapy after 2 and 3 weeks respectively, without any detectable benefit. In patient no. 4, clear tumour progress was detectable at the time of stopping bevacizumab and capecitabine (Table 2).

The median increase in sum of the longest diameter of target lesions at the first staging was 57 mm (range −21 to 139 mm; Table 2, Fig. 1). Median survival without progression after starting bevacizumab/capecitabine was 59 days, and median overall survival was 124 days (Fig. 2). Only two patients had an increase in target tumour mass <25%. Patient no. 2 had stable target lesions after 12 weeks and benefited clinically from bevacizumab and capecitabine. Therefore, therapy was continued despite formally progressive disease due to two new metastases in liver and abdomen. However, after an additional 12 weeks, tumour had progressed tremendously (including multiple new metastases). Patient no. 10 was radiologically stable, but developed acute superior vena cava syndrome after 8 weeks requiring an emergency radiation therapy and was, therefore, judged as progressive disease.

Figure 1
Figure 1

Maximal change (in per cent) from baseline in the sum of the longest diameter of predefined target lesion at the time of first staging during treatment with bevacizumab plus capecitabine in seven evaluable patients with advanced ACC. CT scans have been reviewed centrally by an independent radiologist. Each bar represents one patient. *Indicates patients with new detected metastases. Patient no. 10 developed superior vena cava syndrome and was, therefore, assessed as progressive disease.

Citation: European Journal of Endocrinology 162, 2; 10.1530/EJE-09-0804

Figure 2
Figure 2

Survival without progression and overall survival in ten ACC patients treated with bevacizumab and capecitabine. One patient died outside the pictured timeline 31 months after starting bevacizumab and capecitabine.

Citation: European Journal of Endocrinology 162, 2; 10.1530/EJE-09-0804

With exception of the two cases of therapy limiting hand-foot syndrome, adverse events were minor and treatment was in general well tolerated. Particularly, no episode of hypertension was documented. Regarding the non-specific adverse events like nausea, vomiting or fatigue, we cannot exclude that mitotane has contributed to some of the negative effects. However, since only newly developed events were registered, it is not likely that mitotane is responsible for many of these events (Table 3).

Table 3

Adverse events in ten patients with advanced adrenocortical carcinoma (ACC)a.

EventGrade IGrade IIGrade IIIGrade IV
Fatigue12
Nausea/vomiting3
Fever1
Leucopenia2
Anaemia11
Paraesthesia1
Elevated serum creatinine21
Hand-foot skin reaction2b1c
Rash/desquamation1
Sweating11
Oedema11
Burning mucosa1
Haematuria1

Newly developed during the treatment with bevacizumab and capecitabine (according to NCI-CTG criteria (version 3.0)).

In patient no. 1, therapy was stopped 14 days after starting bevacizumab and capecitabine.

Patient no. 4 suffered from hand-foot, skin reaction grade III, and therapy was therefore, in consideration of radiological proven tumour progression, stopped 21 days after starting bevacizumab and capecitabine.

Discussion

In our patient series, we found no evidence that the combination of bevacizumab and capecitabine is of benefit as salvage therapy for very advanced ACC. The disease was progressing in all patients with a median time to progression of only 59 days. Furthermore, all but one patient died within 9 months after initiation of bevacizumab and capecitabine. Clearly, our patient sample represented a negative selection due to advanced disease stage and several prior systemic treatment regimens. However, the complete lack of response to bevacizumab and capecitabine indicates a very limited potential in patients suffering from advanced ACC.

These disappointing results raise several questions: i) does this study indicate that both bevacizumab and capecitabine are not beneficial in patients with ACC at all? ii) was the relatively low dosage of bevacizumab and capecitabine responsible for the missing effectiveness? iii) does the combination of both drugs have even negative impact on the effects of the individual drugs? iv) would it be more effective to use this combination of drugs in patients not as heavily pretreated as our cohort? Although we cannot answer these questions with certainty, we caution against the assumption that both bevacizumab and capecitabine have in general no effect in patients with ACC. There are several explanations, why the treatment regimen failed: compared to former studies in other tumour entities, the dosage was reduced as a concession to the heavy cytotoxic pretreatment of the patients. Thus, we chose a dosage of 5 mg/kg body weight for bevacizumab every 3 weeks in contrast to 5 mg/kg body weight every 2 weeks used in colorectal cancer added on to the fluorouracil-based chemotherapy (21). In other tumour entities, even higher dosages of 10 mg/kg body weight every 2 weeks are used, and superiority in progression-free survival compared to 3 mg/kg body weight has been shown (24). However, in a compassionate use setting in heavily pretreated patients with progressive malignancy, we aimed at avoiding toxicity. Furthermore, our dosage of 950 mg/m2 capecitabine twice daily remained below the standard recommendation of 1250 mg/m2 twice daily in breast, colorectal or gastric cancer. Capecitabine is absorbed through the intestine and converted to 5′-deoxy-S-fluorouridine (5′-DFUR) and finally, thymidine phosphorylase (TP) converts 5′-DFUR to the active drug 5-FU. This occurs in both tumour and normal tissues; however, TP is found at higher concentrations in most tumour tissue compared with normal healthy tissue. TP expression has been shown to be associated with response to capecitabine in lung cancer (30) and colorectal cancer (31). Although TP activity was detected in ACC (19), we cannot exclude that in advanced disease, dedifferentiation leads to downregulation of TP activity hampering the required conversion into the active compound. Furthermore, with this case series, we cannot verify whether the lack of benefit might be related to pharmacokinetic interactions, but there is no evidence that both drugs interfere with each other. In contrast, data from metastatic colorectal cancer showed a positive effect on progression-free survival by combining bevacizumab and XELOX (capecitabine plus oxaliplatin) versus XELOX alone (27). In addition, it is important to emphasize that our patients had a median of four affected organ sites and had received a median of 4 (range 3–5) prior systemic treatments. These pretreatment regimens might have induced a selection of aggressive dedifferentiated tumour cells not responding to any drugs.

The observed adverse events in our cohort were mainly mild and anticipated. In two patients, treatment had to be stopped due to hand-foot syndrome. This is a common adverse effect of capecitabine, and the percentage of treatment interruptions was not exceptionally high in comparison to other studies. In a meta-analysis of 13 studies, 47% of the patients developed hand-foot syndrome (32).

Our study confirms the disappointing results of salvage therapies in ACC reported in other studies (29, 33, 34). It further demonstrates that the natural course of ACC is progressive and that spontaneous tumour regressions as described for other tumour entities, e.g. melanoma (35), hepatocellular carcinoma (36) or colorectal cancer (37) are extremely unlikely.

We are well aware of the limitations of our study. One of the main drawbacks of our study is that it is not a formal phase II trial. However, until recently, pharmaceutical companies showed no interest to support clinical trials in such a rare disease, and also public funding resources for salvage concepts in rare tumour entities are virtually non-existent. However, our case series has several advantages in comparison with previous case series: the treatment protocol and the evaluation of response were performed prospectively in a standardized manner, and all images were reviewed centralized by an independent radiologist according to RECIST criteria. In addition, the number of reported patients might seem to be low. However, ten patients with clearly progressive disease are probably enough to conclude that bevacizumab plus capecitabine is not effective in ACC refractory to several cytotoxic drug regimes. In this context, it seemed not justifiable to enlarge our series.

In conclusion, we found no benefit of bevacizumab plus capecitabine in pretreated patients with advanced ACC. Therefore, this regimen cannot be recommended as salvage therapy in this disease.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This study was supported by grants of the Deutsche Krebshilfe (grant no. 107111 to M Fassnacht and grant no. 106 080 to B Allolio and M Fassnacht).

Acknowledgements

The case series was only feasible due to the efforts of many colleagues organized in the German Adrenal Network Improving Treatment and Medical Education (GANIMED) network and the German ACC Registry. We are thankful to all colleagues, who followed our protocol suggestion, as most of the therapies were carried out on an outpatient basis, and provided us with the clinical and radiological data of their patients: Cornelia Weiand and Maria Bahlke (Kahl), Waclaw Junikiewicz (Drochtersen), Felix Marquard (Celle), Thorsten Kiencke (Bad Bederkesa), Christina Klawitter (Linum), Stefan Gneipel (Mulda), Wolfgang Schmidt (Raunheim) and Antonius Mutz (Osnabrück). For providing original files of CT and MRI imaging, we thank Gemeinschaftspraxis Radiologie Mainzer Landstrasse&Höchst (Frankfurt), Radiologie, Klinikum Osnabrück, Radiologische Abteilung, Allgemeines Krankenhaus (Celle) and Institut für Radiologie, Charite Campus Mitte (Berlin). We are grateful to Michaela Haaf for her support in running the database of the German ACC Registry. We thank Kathrin Zopf, Clinical Endocrinology, Charité Berlin, for organizational help. We appreciate the immunohistochemical staining and evaluation of four tumour samples with anti-VEGF antibody by Dr Patrick Adam (Department of Pathology of the University of Würzburg).

References

  • 1

    Schteingart DE, Doherty GM, Gauger PG, Giordano TJ, Hammer GD, Korobkin M, Worden FP. Management of patients with adrenal cancer: recommendations of an international consensus conference. Endocrine-Related Cancer 2005 12 667680.

    • Search Google Scholar
    • Export Citation
  • 2

    Icard P, Goudet P, Charpenay C, Andreassian B, Carnaille B, Chapuis Y, Cougard P, Henry JF, Proye C. Adrenocortical carcinomas: surgical trends and results of a 253-patient series from the French Association of Endocrine Surgeons study group. World Journal of Surgery 2001 25 891897.

    • Search Google Scholar
    • Export Citation
  • 3

    Vassilopoulou-Sellin R, Schultz PN. Adrenocortical carcinoma. Clinical outcome at the end of the 20th century. Cancer 2001 92 11131121.

  • 4

    Allolio B, Fassnacht M. Clinical review: adrenocortical carcinoma: clinical update. Journal of Clinical Endocrinology and Metabolism 2006 91 20272037.

    • Search Google Scholar
    • Export Citation
  • 5

    Abiven G, Coste J, Groussin L, Anract P, Tissier F, Legmann P, Dousset B, Bertagna X, Bertherat J. Clinical and biological features in the prognosis of adrenocortical cancer: poor outcome of cortisol-secreting tumors in a series of 202 consecutive patients. Journal of Clinical Endocrinology and Metabolism 2006 91 26502655.

    • Search Google Scholar
    • Export Citation
  • 6

    Assie G, Antoni G, Tissier F, Caillou B, Abiven G, Gicquel C, Leboulleux S, Travagli JP, Dromain C, Bertagna X, Bertherat J, Schlumberger M, Baudin E. Prognostic parameters of metastatic adrenocortical carcinoma. Journal of Clinical Endocrinology and Metabolism 2007 92 148154.

    • Search Google Scholar
    • Export Citation
  • 7

    Libe R, Fratticci A, Bertherat J. Adrenocortical cancer: pathophysiology and clinical management. Endocrine-Related Cancer 2007 14 1328.

  • 8

    Terzolo M, Angeli A, Fassnacht M, Daffara F, Tauchmanova L, Conton PA, Rossetto R, Buci L, Sperone P, Grossrubatscher E, Reimondo G, Bollito E, Papotti M, Saeger W, Hahner S, Koschker AC, Arvat E, Ambrosi B, Loli P, Lombardi G, Mannelli M, Bruzzi P, Mantero F, Allolio B, Dogliotti L, Berruti A. Adjuvant mitotane treatment for adrenocortical carcinoma. New England Journal of Medicine 2007 356 23722380.

    • Search Google Scholar
    • Export Citation
  • 9

    Bilimoria KY, Shen WT, Elaraj D, Bentrem DJ, Winchester DJ, Kebebew E, Sturgeon C. Adrenocortical carcinoma in the United States: treatment utilization and prognostic factors. Cancer 2008 113 31303136.

    • Search Google Scholar
    • Export Citation
  • 10

    Fassnacht M, Johanssen S, Quinkler M, Bucsky P, Willenberg HS, Beuschlein F, Terzolo M, Mueller HH, Hahner S, Allolio B. Limited prognostic value of the 2004 International Union Against Cancer staging classification for adrenocortical carcinoma: proposal for a Revised TNM Classification. Cancer 2009 115 243250.

    • Search Google Scholar
    • Export Citation
  • 11

    Fassnacht M, Allolio B. Clinical management of adrenocortical carcinoma. Best Practice and Research. Clinical Endocrinology and Metabolism 2009 23 273289.

    • Search Google Scholar
    • Export Citation
  • 12

    Fassnacht M, Hahner S, Polat B, Koschker AC, Kenn W, Flentje M, Allolio B. Efficacy of adjuvant radiotherapy of the tumor bed on local recurrence of adrenocortical carcinoma. Journal of Clinical Endocrinology and Metabolism 2006 91 45014504.

    • Search Google Scholar
    • Export Citation
  • 13

    Berruti A, Terzolo M, Sperone P, Pia A, Casa SD, Gross DJ, Carnaghi C, Casali P, Porpiglia F, Mantero F, Reimondo G, Angeli A, Dogliotti L. Etoposide, doxorubicin and cisplatin plus mitotane in the treatment of advanced adrenocortical carcinoma: a large prospective phase II trial. Endocrine-Related Cancer 2005 12 657666.

    • Search Google Scholar
    • Export Citation
  • 14

    Khan TS, Imam H, Juhlin C, Skogseid B, Grondal S, Tibblin S, Wilander E, Oberg K, Eriksson B. Streptozocin and o,p'DDD in the treatment of adrenocortical cancer patients: long-term survival in its adjuvant use. Annals of Oncology 2000 11 12811287.

    • Search Google Scholar
    • Export Citation
  • 15

    Koschker AC, Fassnacht M, Hahner S, Weismann D, Allolio B. Adrenocortical carcinoma – improving patient care by establishing new structures. Experimental and Clinical Endocrinology and Diabetes 2006 114 4551.

    • Search Google Scholar
    • Export Citation
  • 16

    Zacharieva S, Atanassova I, Orbetzova M, Nachev E, Kalinov K, Kirilov G, Shigarminova R, Ivanova R, Dashev G. Circulating vascular endothelial growth factor and active renin concentrations and prostaglandin E2 urinary excretion in patients with adrenal tumours. European Journal of Endocrinology 2004 150 345349.

    • Search Google Scholar
    • Export Citation
  • 17

    Kirschner LS. Emerging treatment strategies for adrenocortical carcinoma: a new hope. Journal of Clinical Endocrinology 2005 91 1421.

  • 18

    Fassnacht M, Kreissl MC, Weismann D, Allolio B. New targets and therapeutic approaches for endocrine malignancies. Pharmacology & Therapeutics 2009 123 117141.

    • Search Google Scholar
    • Export Citation
  • 19

    de Fraipont F, El Atifi M, Gicquel C, Bertagna X, Chambaz EM, Feige JJ. Expression of the angiogenesis markers vascular endothelial growth factor-A, thrombospondin-1, and platelet-derived endothelial cell growth factor in human sporadic adrenocortical tumors: correlation with genotypic alterations. Journal of Clinical Endocrinology and Metabolism 2000 85 47344741.

    • Search Google Scholar
    • Export Citation
  • 20

    Kolomecki K, Stepien H, Bartos M, Kuzdak K. Usefulness of VEGF, MMP-2, MMP-3 and TIMP-2 serum level evaluation in patients with adrenal tumours. Endocrine Regulations 2001 35 916.

    • Search Google Scholar
    • Export Citation
  • 21

    Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. New England Journal of Medicine 2004 350 23352342.

    • Search Google Scholar
    • Export Citation
  • 22

    Ramaswamy B, Elias AD, Kelbick NT, Dodley A, Morrow M, Hauger M, Allen J, Rhoades C, Kendra K, Chen HX, Eckhardt SG, Shapiro CL. Phase II trial of bevacizumab in combination with weekly docetaxel in metastatic breast cancer patients. Clinical Cancer Research 2006 12 31243129.

    • Search Google Scholar
    • Export Citation
  • 23

    Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. New England Journal of Medicine 2006 355 25422550.

    • Search Google Scholar
    • Export Citation
  • 24

    Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, Steinberg SM, Chen HX, Rosenberg SA. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. New England Journal of Medicine 2003 349 427434.

    • Search Google Scholar
    • Export Citation
  • 25

    Montoya M, Brown JW, Fishman LM. Comparative effects of chemotherapeutic agents on the growth and survival of human adrenal carcinoma cells in culture. Hormone and Metabolic Research 2008 40 302305.

    • Search Google Scholar
    • Export Citation
  • 26

    Cassidy J, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzen F, Saltz L. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. Journal of Clinical Oncology 2008 26 20062012.

    • Search Google Scholar
    • Export Citation
  • 27

    Saltz LB, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzen F, Cassidy J. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. Journal of Clinical Oncology 2008 26 20132019.

    • Search Google Scholar
    • Export Citation
  • 28

    Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG. 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. Journal of the National Cancer Institute 2000 92 205216.

    • Search Google Scholar
    • Export Citation
  • 29

    Quinkler M, Hahner S, Wortmann S, Johanssen S, Adam P, Ritter C, Strasburger C, Allolio B, Fassnacht M. Treatment of advanced adrenocortical carcinoma with erlotinib plus gemcitabine. Journal of Clinical Endocrinology and Metabolism 2008 93 20572062.

    • Search Google Scholar
    • Export Citation
  • 30

    Han JY, Hong EK, Lee SY, Yoon SM, Lee DH, Lee JS. Thymidine phosphorylase expression in tumour cells and tumour response to capecitabine plus docetaxel chemotherapy in non-small cell lung cancer. Journal of Clinical Pathology 2005 58 650654.

    • Search Google Scholar
    • Export Citation
  • 31

    Uchida K, Danenberg PV, Danenberg KD, Grem JL. Thymidylate synthase, dihydropyrimidine dehydrogenase, ERCC1, and thymidine phosphorylase gene expression in primary and metastatic gastrointestinal adenocarcinoma tissue in patients treated on a phase I trial of oxaliplatin and capecitabine. BMC Cancer 2008 8 386.

    • Search Google Scholar
    • Export Citation
  • 32

    Summary of product characteristics of capecitabine (Xeloda(R)) by Roche Registration Limited, UK. 2008.

  • 33

    Baudin E, Docao C, Gicquel C, Vassal G, Bachelot A, Penfornis A, Schlumberger M. Use of a topoisomerase I inhibitor (irinotecan, CPT-11) in metastatic adrenocortical carcinoma. Annals of Oncology 2002 13 18061809.

    • Search Google Scholar
    • Export Citation
  • 34

    Khan TS, Sundin A, Juhlin C, Wilander E, Oberg K, Eriksson B. Vincristine, cisplatin, teniposide, and cyclophosphamide combination in the treatment of recurrent or metastatic adrenocortical cancer. Medical Oncology 2004 21 167177.

    • Search Google Scholar
    • Export Citation
  • 35

    Kalialis LV, Drzewiecki KT, Mohammadi M, Mehlsen AB, Klyver H. Spontaneous regression of metastases from malignant melanoma: a case report. Melanoma Research 2008 18 279283.

    • Search Google Scholar
    • Export Citation
  • 36

    Oquinena S, Inarrairaegui M, Vila JJ, Alegre F, Zozaya JM, Sangro B. Spontaneous regression of hepatocellular carcinoma: three case reports and a categorized review of the literature. Digestive Diseases and Sciences 2009 54 11471153.

    • Search Google Scholar
    • Export Citation
  • 37

    Abdelrazeq AS. Spontaneous regression of colorectal cancer: a review of cases from 1900 to 2005. International Journal of Colorectal Disease 2007 22 727736.

    • Search Google Scholar
    • Export Citation

If the inline PDF is not rendering correctly, you can download the PDF file here.

 

     European Society of Endocrinology

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 1055 213 17
PDF Downloads 480 203 23
  • View in gallery

    Maximal change (in per cent) from baseline in the sum of the longest diameter of predefined target lesion at the time of first staging during treatment with bevacizumab plus capecitabine in seven evaluable patients with advanced ACC. CT scans have been reviewed centrally by an independent radiologist. Each bar represents one patient. *Indicates patients with new detected metastases. Patient no. 10 developed superior vena cava syndrome and was, therefore, assessed as progressive disease.

  • View in gallery

    Survival without progression and overall survival in ten ACC patients treated with bevacizumab and capecitabine. One patient died outside the pictured timeline 31 months after starting bevacizumab and capecitabine.

  • 1

    Schteingart DE, Doherty GM, Gauger PG, Giordano TJ, Hammer GD, Korobkin M, Worden FP. Management of patients with adrenal cancer: recommendations of an international consensus conference. Endocrine-Related Cancer 2005 12 667680.

    • Search Google Scholar
    • Export Citation
  • 2

    Icard P, Goudet P, Charpenay C, Andreassian B, Carnaille B, Chapuis Y, Cougard P, Henry JF, Proye C. Adrenocortical carcinomas: surgical trends and results of a 253-patient series from the French Association of Endocrine Surgeons study group. World Journal of Surgery 2001 25 891897.

    • Search Google Scholar
    • Export Citation
  • 3

    Vassilopoulou-Sellin R, Schultz PN. Adrenocortical carcinoma. Clinical outcome at the end of the 20th century. Cancer 2001 92 11131121.

  • 4

    Allolio B, Fassnacht M. Clinical review: adrenocortical carcinoma: clinical update. Journal of Clinical Endocrinology and Metabolism 2006 91 20272037.

    • Search Google Scholar
    • Export Citation
  • 5

    Abiven G, Coste J, Groussin L, Anract P, Tissier F, Legmann P, Dousset B, Bertagna X, Bertherat J. Clinical and biological features in the prognosis of adrenocortical cancer: poor outcome of cortisol-secreting tumors in a series of 202 consecutive patients. Journal of Clinical Endocrinology and Metabolism 2006 91 26502655.

    • Search Google Scholar
    • Export Citation
  • 6

    Assie G, Antoni G, Tissier F, Caillou B, Abiven G, Gicquel C, Leboulleux S, Travagli JP, Dromain C, Bertagna X, Bertherat J, Schlumberger M, Baudin E. Prognostic parameters of metastatic adrenocortical carcinoma. Journal of Clinical Endocrinology and Metabolism 2007 92 148154.

    • Search Google Scholar
    • Export Citation
  • 7

    Libe R, Fratticci A, Bertherat J. Adrenocortical cancer: pathophysiology and clinical management. Endocrine-Related Cancer 2007 14 1328.

  • 8

    Terzolo M, Angeli A, Fassnacht M, Daffara F, Tauchmanova L, Conton PA, Rossetto R, Buci L, Sperone P, Grossrubatscher E, Reimondo G, Bollito E, Papotti M, Saeger W, Hahner S, Koschker AC, Arvat E, Ambrosi B, Loli P, Lombardi G, Mannelli M, Bruzzi P, Mantero F, Allolio B, Dogliotti L, Berruti A. Adjuvant mitotane treatment for adrenocortical carcinoma. New England Journal of Medicine 2007 356 23722380.

    • Search Google Scholar
    • Export Citation
  • 9

    Bilimoria KY, Shen WT, Elaraj D, Bentrem DJ, Winchester DJ, Kebebew E, Sturgeon C. Adrenocortical carcinoma in the United States: treatment utilization and prognostic factors. Cancer 2008 113 31303136.

    • Search Google Scholar
    • Export Citation
  • 10

    Fassnacht M, Johanssen S, Quinkler M, Bucsky P, Willenberg HS, Beuschlein F, Terzolo M, Mueller HH, Hahner S, Allolio B. Limited prognostic value of the 2004 International Union Against Cancer staging classification for adrenocortical carcinoma: proposal for a Revised TNM Classification. Cancer 2009 115 243250.

    • Search Google Scholar
    • Export Citation
  • 11

    Fassnacht M, Allolio B. Clinical management of adrenocortical carcinoma. Best Practice and Research. Clinical Endocrinology and Metabolism 2009 23 273289.

    • Search Google Scholar
    • Export Citation
  • 12

    Fassnacht M, Hahner S, Polat B, Koschker AC, Kenn W, Flentje M, Allolio B. Efficacy of adjuvant radiotherapy of the tumor bed on local recurrence of adrenocortical carcinoma. Journal of Clinical Endocrinology and Metabolism 2006 91 45014504.

    • Search Google Scholar
    • Export Citation
  • 13

    Berruti A, Terzolo M, Sperone P, Pia A, Casa SD, Gross DJ, Carnaghi C, Casali P, Porpiglia F, Mantero F, Reimondo G, Angeli A, Dogliotti L. Etoposide, doxorubicin and cisplatin plus mitotane in the treatment of advanced adrenocortical carcinoma: a large prospective phase II trial. Endocrine-Related Cancer 2005 12 657666.

    • Search Google Scholar
    • Export Citation
  • 14

    Khan TS, Imam H, Juhlin C, Skogseid B, Grondal S, Tibblin S, Wilander E, Oberg K, Eriksson B. Streptozocin and o,p'DDD in the treatment of adrenocortical cancer patients: long-term survival in its adjuvant use. Annals of Oncology 2000 11 12811287.

    • Search Google Scholar
    • Export Citation
  • 15

    Koschker AC, Fassnacht M, Hahner S, Weismann D, Allolio B. Adrenocortical carcinoma – improving patient care by establishing new structures. Experimental and Clinical Endocrinology and Diabetes 2006 114 4551.

    • Search Google Scholar
    • Export Citation
  • 16

    Zacharieva S, Atanassova I, Orbetzova M, Nachev E, Kalinov K, Kirilov G, Shigarminova R, Ivanova R, Dashev G. Circulating vascular endothelial growth factor and active renin concentrations and prostaglandin E2 urinary excretion in patients with adrenal tumours. European Journal of Endocrinology 2004 150 345349.

    • Search Google Scholar
    • Export Citation
  • 17

    Kirschner LS. Emerging treatment strategies for adrenocortical carcinoma: a new hope. Journal of Clinical Endocrinology 2005 91 1421.

  • 18

    Fassnacht M, Kreissl MC, Weismann D, Allolio B. New targets and therapeutic approaches for endocrine malignancies. Pharmacology & Therapeutics 2009 123 117141.

    • Search Google Scholar
    • Export Citation
  • 19

    de Fraipont F, El Atifi M, Gicquel C, Bertagna X, Chambaz EM, Feige JJ. Expression of the angiogenesis markers vascular endothelial growth factor-A, thrombospondin-1, and platelet-derived endothelial cell growth factor in human sporadic adrenocortical tumors: correlation with genotypic alterations. Journal of Clinical Endocrinology and Metabolism 2000 85 47344741.

    • Search Google Scholar
    • Export Citation
  • 20

    Kolomecki K, Stepien H, Bartos M, Kuzdak K. Usefulness of VEGF, MMP-2, MMP-3 and TIMP-2 serum level evaluation in patients with adrenal tumours. Endocrine Regulations 2001 35 916.

    • Search Google Scholar
    • Export Citation
  • 21

    Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. New England Journal of Medicine 2004 350 23352342.

    • Search Google Scholar
    • Export Citation
  • 22

    Ramaswamy B, Elias AD, Kelbick NT, Dodley A, Morrow M, Hauger M, Allen J, Rhoades C, Kendra K, Chen HX, Eckhardt SG, Shapiro CL. Phase II trial of bevacizumab in combination with weekly docetaxel in metastatic breast cancer patients. Clinical Cancer Research 2006 12 31243129.

    • Search Google Scholar
    • Export Citation
  • 23

    Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. New England Journal of Medicine 2006 355 25422550.

    • Search Google Scholar
    • Export Citation
  • 24

    Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, Steinberg SM, Chen HX, Rosenberg SA. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. New England Journal of Medicine 2003 349 427434.

    • Search Google Scholar
    • Export Citation
  • 25

    Montoya M, Brown JW, Fishman LM. Comparative effects of chemotherapeutic agents on the growth and survival of human adrenal carcinoma cells in culture. Hormone and Metabolic Research 2008 40 302305.

    • Search Google Scholar
    • Export Citation
  • 26

    Cassidy J, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzen F, Saltz L. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. Journal of Clinical Oncology 2008 26 20062012.

    • Search Google Scholar
    • Export Citation
  • 27

    Saltz LB, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzen F, Cassidy J. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. Journal of Clinical Oncology 2008 26 20132019.

    • Search Google Scholar
    • Export Citation
  • 28

    Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG. 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. Journal of the National Cancer Institute 2000 92 205216.

    • Search Google Scholar
    • Export Citation
  • 29

    Quinkler M, Hahner S, Wortmann S, Johanssen S, Adam P, Ritter C, Strasburger C, Allolio B, Fassnacht M. Treatment of advanced adrenocortical carcinoma with erlotinib plus gemcitabine. Journal of Clinical Endocrinology and Metabolism 2008 93 20572062.

    • Search Google Scholar
    • Export Citation
  • 30

    Han JY, Hong EK, Lee SY, Yoon SM, Lee DH, Lee JS. Thymidine phosphorylase expression in tumour cells and tumour response to capecitabine plus docetaxel chemotherapy in non-small cell lung cancer. Journal of Clinical Pathology 2005 58 650654.

    • Search Google Scholar
    • Export Citation
  • 31

    Uchida K, Danenberg PV, Danenberg KD, Grem JL. Thymidylate synthase, dihydropyrimidine dehydrogenase, ERCC1, and thymidine phosphorylase gene expression in primary and metastatic gastrointestinal adenocarcinoma tissue in patients treated on a phase I trial of oxaliplatin and capecitabine. BMC Cancer 2008 8 386.

    • Search Google Scholar
    • Export Citation
  • 32

    Summary of product characteristics of capecitabine (Xeloda(R)) by Roche Registration Limited, UK. 2008.

  • 33

    Baudin E, Docao C, Gicquel C, Vassal G, Bachelot A, Penfornis A, Schlumberger M. Use of a topoisomerase I inhibitor (irinotecan, CPT-11) in metastatic adrenocortical carcinoma. Annals of Oncology 2002 13 18061809.

    • Search Google Scholar
    • Export Citation
  • 34

    Khan TS, Sundin A, Juhlin C, Wilander E, Oberg K, Eriksson B. Vincristine, cisplatin, teniposide, and cyclophosphamide combination in the treatment of recurrent or metastatic adrenocortical cancer. Medical Oncology 2004 21 167177.

    • Search Google Scholar
    • Export Citation
  • 35

    Kalialis LV, Drzewiecki KT, Mohammadi M, Mehlsen AB, Klyver H. Spontaneous regression of metastases from malignant melanoma: a case report. Melanoma Research 2008 18 279283.

    • Search Google Scholar
    • Export Citation
  • 36

    Oquinena S, Inarrairaegui M, Vila JJ, Alegre F, Zozaya JM, Sangro B. Spontaneous regression of hepatocellular carcinoma: three case reports and a categorized review of the literature. Digestive Diseases and Sciences 2009 54 11471153.

    • Search Google Scholar
    • Export Citation
  • 37

    Abdelrazeq AS. Spontaneous regression of colorectal cancer: a review of cases from 1900 to 2005. International Journal of Colorectal Disease 2007 22 727736.

    • Search Google Scholar
    • Export Citation