Treatment of Refractory Adrenocortical Carcinoma with Thalidomide: Analysis of 27 Patients from the European Network for the Study of Adrenal Tumours Registry
Authors
Matthias Kroiss1 ”, Timo Deutschbein1”, Wiebke Schlotelburg2, Cristina Lucia Ronchi1, Ségolène Hescot3, Daniela Körbl1, Felix Megerle1, Felix Beuschlein4, 5, Bruno Neu6, Marcus Quinkler7, Eric Baudin3, Stefanie Hahner1, Anke Heidemeier2, Martin Fassnacht1, 8
Affiliations
1 Department of Internal Medicine I, Endocrine and Diabetes Unit, University Hospital Würzburg, University of Würzburg, Germany
2 Department of Radiology, University Hospital Würzburg, University of Würzburg, Germany
3
Gustave Roussy, Université Paris Sud, France
4 Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany
5 Klinik für Endokrinologie, Diabetologie und Klinische Ernährung, Universitätsspital Zürich, Zürich, Switzerland
6 Second Department of Medicine, Acedemic Teaching Hospital Landshut Achdorf, Germany
7 Endocrinology in Charlottenburg, Berlin, Germany
8 Comprehensive Cancer Center Mainfranken, University of Würzburg, Germany
Key words
adrenal, adverse events, cancer, efficacy, follow-up, outcome, progression, side-effects, staging, toxicity, treatment
| received | 12.07.2018 |
| revised | 20.08.2018 |
| accepted | 19.09.2018 |
Bibliography
DOI https://doi.org/10.1055/a-0747-5571 Published online: 2018
Exp Clin Endocrinol Diabetes @ J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart New York ISSN 0947-7349
Correspondence
Matthias Kroiss, MD, PhD Department of Internal Medicine I Division of Endocrinology and Diabetology University Hospital Würzburg University of Würzburg Oberdürrbacher Str. 6 97080 Würzburg Germany Tel .: +49/931/201 39740, Fax: +49/931/201 639740 Kroiss_m@ukw.de
ABSTRACT
Objective Adrenocortical carcinoma (ACC) is a rare malig- nancy with a dismal prognosis. In advanced stages, tumour control by mitotane and cytotoxic chemotherapy is often tem- porary and salvage treatments are warranted.
Methods Retrospective cohort study of participants in the prospective European Networks for the Study of Adrenal Tu- mours (ENSAT) registry. Main outcome measures were best response during treatment, progression-free survival (PFS), both measured according to RECIST 1.1 by two blinded radi- ologists, and overall survival (OS).
Results Twenty-seven patients (13 males; median age 44.1 years) progressing after mitotane and a median of 4 further systemic treatments were included. Thalidomide was admin- istered as tolerated with a starting dose of 50 mg and target dose of 200 mg /d. The median interval between treatment initiation and first imaging was 10.5 (4.4-17.5) weeks. The best response to treatment was stable disease (SD, n=2) and pro- gressive disease (n =25), with a median PFS of 11.2 weeks and a median OS of 36.4 weeks. The first patient with SD discontin- ued treatment due to mild epistaxis and diarrhea after 22.3 weeks. The second patient had SD at the second treatment evaluation after 25.2 weeks and continued thalidomide but then had clinical progression and deceased after 54.3 weeks. In general, thalidomide induced only mild or moderate adverse effects (mainly fatigue and gastrointestinal complaints).
Conclusion Thalidomide was overall well tolerated but result- ed in disease control in only 2/27 (7.4%) patients. In the absence of predictive response markers, thalidomide should only be considered in exceptional cases as a salvage therapy in ACC.
* M.K. and T.D. contributed equally to this work
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Abbreviations
ACC adrenocortical carcinoma
CT computed tomography
CTC Common Toxicity Criteria
ECOG Eastern Cooperative Oncology Group
ENSAT European Network for the Study of Adrenal Tumours
OS overall survival
PFS progression-free survival
RECIST Response Evaluation Criteria In Solid Tumours
Introduction
Adrenocortical carcinoma (ACC) is an orphan malignancy with a dismal prognosis [1-4]. Complete tumour removal is still the only potentially curative option and is the initial treatment of choice in localized disease [5-7]. While the role of surgery in advanced dis- ease remains controversial [8-11], the adrenostatic agent mito- tane is regarded as the cornerstone of medical therapy in advanced disease and in adjuvant treatment of high-grade ACC [12-18]. The first phase III clinical trial in ACC established mitotane plus combi- nation chemotherapy with etoposide, doxorubicin, and cisplatin as standard of care for the treatment of advanced cases [19]. Other cytotoxic chemotherapy regimens include gemcitabine/capecit- abine [20, 21] and streptozotocin [22]. In tumours refractory to cy- totoxic chemotherapy, however, treatment options are still scarce. Over the last decade, several cytotoxic and molecular targeted ther- apies have been evaluated as potential alternatives [23-28] but failed to reach significant improvement [29]. In the absence of es- tablished treatments, thalidomide has attracted some interest. His- torically prescribed as a hypnotic agent, it was soon banned due to its high teratogenic potential. Extensive research led to recognition of the anti-angiogenic and immunomodulatory properties of the drug, resulting in its renaissance as an effective therapy for leprosy and multiple myeloma for which it is approved in combination with melphalan and prednisone [30-33]. An encouraging case report published in 2005 showed an impressive tumour response in a fe- male patient with advanced ACC [34]. Another series described a decrease of tumour burden in four of six ACC patients treated with thalidomide (either alone or in combination with other mitotane or systemic chemotherapy) [35]. This resulted in subsequent use of thalidomide as an off-label treatment in selected patients suf- fering from refractory ACC. Unfortunately the success rate of this salvage therapy has never been investigated. Hence, we hereby aimed at determining the efficacy and tolerability of thalidomide in patients with refractory ACC who were prospectively enrolled in the European Network for the Study of Adrenal Tumours (ENSAT) Registry.
Subjects and Methods
Patients
Patients and clinical parameters (e. g. sex, age at initial diagnosis, evidence of hormone excess, size of the primary tumour, tumour stage according to the ENSAT classification [36], Weiss score [37], Ki67 index [38, 39], date of documented irresectability and subse-
quent therapies, presence and number of distant metastases, con- comitant treatment with mitotane, and detailed follow-up infor- mation) were retrieved from the German ACC Registry and the ENSAT Registry (www.ensat.org/registry). Both registries have been approved by the ethics committee of the University of Würzburg (approval numbers 86/03, and 88/11, respectively). To be included into the study, patient had to fulfill the following crite- ria at the time of treatment initiation with thalidomide: age ≥18 years, histologically confirmed ACC, written informed consent, re- fractory and measurable progressive disease at baseline, no prior therapy with thalidomide, treatment with thalidomide for at least 30 days.
Treatment evaluation
In 24 cases (89%), tumour response was radiologically assessed prior to treatment and from the beginning of treatment until tu- mour progression, using the Response Evaluation Criteria In Solid Tumours (RECIST) guideline version 1.1 for interpretation of imag- ing results [40]. For this, all imaging studies were individually re- viewed in a blinded fashion by two experienced radiologists (A.H., W.S.). Follow-up imaging after initiation of thalidomide was not performed in three patients with severe tumour progression; these cases were only clinically evaluated. Adverse drug effects consid- ered to be treatment related were retrieved from patient records and graded according to the National Cancer Institute Common Toxicity Criteria (CTC) version 4.0. In uncertain cases, the physician who originally supervised the treatment was contacted to clarify potential adverse events. Adverse drug effects at least considered possibly treatment-related are reported in this study.
Statistical analysis
Progression-free survival was defined as the interval between the beginning of thalidomide treatment and the date at which progres- sive disease was documented at imaging, clinically (e. g. treatment discontinuation due to severely impaired general condition or ad- verse effects), or death of any cause. Overall survival was calculat- ed as the time between start of thalidomide and death of any cause or last follow-up. Survival curves were constructed using the Kaplan-Meier method. Continuous variables are presented as the median and range and Kaplan-Meier curves as the median and 95 % confidence interval unless otherwise stated. Statistical significance was taken as p<0.05. GraphPad Prism 6.0 software (GraphPad Soft- ware Inc., San Diego, USA) was used for statistical calculations.
Results
Patient characteristics
At the time of the final analysis (January 2018), 27 patients fulfill- ing the inclusion criteria were identified (pertinent data are given in Table 1). Patients were treated with thalidomide between 2005 and 2017 in 4 European centers participating in the ENSAT Regis- try. At the time of treatment initiation, all except one patient had undergone surgical resection (with 13 subjects having at least one surgical re-intervention). Systemic pretreatment was mitotane in all 27 patients (100%); 21 patients (78%) had at least three prior systemic therapies in addition to mitotane (median of 4 further
| Characteristic | Number (%) of patients or median (range) |
|---|---|
| Number of patients | 27 |
| Female Sex | 14 (52%) |
| Age at initial diagnosis (years) | 44.1 (22.7-64.4) |
| ENSAT tumour stage at initial diagnosis | |
| II | 13 (48) |
| III | 6 (22) |
| IV | 8 (30) |
| Main endocrine activity at initial diagnosis | |
| Glucocorticoid excess | 12 (44) |
| Androgen excess | 5 (19) |
| Mineralocorticoid excess | 1 (4) |
| None or not documented | 9 (33) |
| Surgical interventions (number) | |
| Median (range) | 1 (0-6) |
| Histopathology | |
| highest Ki67 (n=24)<10% | 8 (33) |
| 10-19% | 6 (25) |
| ≥20% | 10 (42) |
| Weiss score (n= 17) | 6 (4-9) |
| Therapy prior to treatment with thalidomide | |
| Mitotane | 27 (100) |
| - continued at the time of thalidomide initiation | 13 (48 %) |
| - Median plasma level at the time of thalidomide initiation (mg/l, n = 13) | 14.5 (3.5 - 17.6) |
| Cytotoxic chemotherapy | 24 (89) |
| - Etoposide, Doxorubicin, Cisplatin | 22 (81) |
| - Streptozotocin | 22 (81) |
| - Gemcitabine, Capecitabine | 20 (74) |
| - Trofosfamide | 13 (48) |
| - Etoposide, Cisplatin | 2 (7) |
| - Etoposide, Carboplatin | 1 (4) |
| - Gemcitabine, Carboplatin | 1 (4) |
| - Doxorubicin, Paclitaxel | 1 (4) |
| Targeted therapy | 5 (19) |
| - Linsitinib | 3 (11) |
| - Sunitinib | 2 (7) |
| Combined cytotoxic and targeted therapy | 1 (4) |
| - Capecitabine, vevacizumab | 1 (4) |
| Radiotherapy | 9 (33) |
| Chemoembolization | 4 (15) |
| Radio frequency ablation | 3 (11) |
| 131I-Iodometomidate | 1 (4) |
| None | 0 (0) |
| Interval between the initial diagnosis and thalidomide initiation (months) Median (range) | 36.0 (6.0-98.9) |
| Interval between the diagnosis of metastasized ACC and thalidomide initiation (months) Median (range) | 25.2 (0.0-72.4) |
| Age at thalidomide initiation (years) Median (range) | 46.9 (24.2-69.0) |
| Tumor burden at thalidomide initiation | |
| Distant metastasis (multiple lesions) | 12 |
| Combination of local recurrence and multiple metastases | 9 |
| Unknown | 6 |
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PID 17
100
Progression-free survival (%)
80
60
40
20
PID 3
0
0
5
10
15
20
25
Time to event (weeks)
100
Overall survival (%)
80
60
40
20
0
0
50
100
150
Time to event (weeks)
systemic treatments), while three patients (11 %) had declined any cytotoxic chemotherapy and were pretreated only with mitotane. The median intervals between initiation of thalidomide and the in- itial diagnosis of ACC or the first documentation of metastatic dis- ease were 36.0 months (range 6.0-98.9 months) and 25.2 months (range 0.0 to 72.5 months), respectively.
Tumour response and survival analysis
Patients were initially treated with a median thalidomide dosage of 100 mg/d (range 50 to 200 mg/d), usually given once daily. Tha- lidomide was adjusted according to tolerability and toxicity aiming at a target dosage of 200mg/d. In a single patient, thalidomide was reduced from 200 to 100 mg per day because of CTC grade II fa- tigue. Conversely, dosages were increased in 11 patients to a max- imum of 400 mg/d in a single patient. One patient refused to in- crease the dosage >50 mg/d due to the perceived risk of adverse
effects. The median interval between treatment initiation and sub- sequent staging was 10.5 weeks (range 4.4 to 17.5 weeks). Best response to treatment was stable disease in two patients, whereas 25 patients experienced progressive disease already at the time of their first imaging. The median progression-free survival was 11.2 weeks (range 4.4 to 22.8 weeks, > Fig. 1). The first patient with stable disease refused continuation of treatment due to mild epistaxis and diarrhea after 22.3 weeks and progressed finally after 34.8 weeks. The second patient had stable disease according to RE- CIST criteria at the second staging on treatment after 25.2 weeks. This treatment evaluation was performed by 18-fluorodeoxyglu- cose positron emission tomography (F-18-FDG-PET-CT) and re- vealed increased tracer uptake of one bone lesion that was previ- ously barely detectable. The patient continued treatment despite clinical suspicion of tumour progression (bone pain) without inter- im imaging for 41.6 weeks and died from ACC 54.3 weeks after treatment initiation. Of note, prior thalidomide he had progressed to 4 different cytotoxic regimens after a duration of 17 (EDP), 13 (gemcitabine/capecitabine), 9 (streptozotocin), and 26 (trofosfa- mide) weeks. This patient received a thalidomide dose of only 50 mg/d since he declined a higher dosage. Mitotane had been dis- continued before thalidomide.
At the time of evaluation, all patients have deceased and medi- an OS is 36.4 weeks (range 5.1 to 111.1 weeks, » Fig. 2).
Treatment related toxicity
Retrospective information about tolerability was available in 25 pa- tients (93%). Relatively mild treatment related symptoms (i. e., CTC grades I and II) were observed in 14 patients, whereas 4 patients experienced more severe adverse events (i. e., CTC grade III). For the remaining 7 patients, no treatment-related side-effects were recorded. Details are given in » Table 2.
Description of two remarkable cases
We observed only two cases with disease stabilization. In the first patient, thalidomide was stopped due to adverse effects (i. e. epistaxis and diarrhea). The second patient had disease stabiliza- tion at the second treatment evaluation and continued treatment without further tumour evaluation until his death in the 42nd week of treatment at a dose of only 50 mg thalidomide. This patient was diagnosed with an ENSAT stage II ACC 4.3 years before initiation of thalidomide. The primary tumour had a very low Ki67 index of only 2% and a corresponding Weiss score of 4; biochemically, an andro- gen excess was observed. Despite these features, advanced disease was diagnosed after one year. Apart from local recurrence, metas- tases were present in both lungs, the peritoneum, and bones (with the latter presenting as diffuse osteolytic metastasis). Of note, ex- tra-osseous tumour lesions were radiologically stable at the first and second radiologic evaluation on thalidomide. However, there was also increasing FDG-uptake in a bone lesion which was retro- spectively present at the initial staging on therapy. Bone metasta- ses during continued thalidomide showed clinical progression, resulting in a pathological fracture which required surgical stabili- zation. Hence, overall disease course was characterized by uncon- trolled bone metastases and it is uncertain whether stable disease of measurable tumour lesions really reflected a treatment related effect.
| CTC category | Side-effects (in alphabetical order) | CTC Grade 1 - 2 (n) | CTC Grade 3 - 4 (n) |
|---|---|---|---|
| Blood and lymphatic system | Anemia | 1 | |
| Gastrointestinal | Constipation | 1 | |
| Decreased appetite | 1 | ||
| Diarrhea | 3 | ||
| Ileal obstruction | 1 | ||
| Nausea | 1 | ||
| General disorders | Asthenia | 5 | |
| Changes of body weight (loss or gain) | 2 | ||
| Edema (limb or trunk) | 2 | ||
| Fatigue | 11 | 1 | |
| Pain (any) | 4 | ||
| Laboratory investigations | Increased creatinine | ||
| Nervous system disorders | Dizziness | 1 | |
| Paresthesia | 2 | ||
| Respiratory, thoracic and mediastinal | Dyspnea | 1 | |
| Epistaxis | 1 | ||
| Skin and subcutaneous tissue | Dry skin | 1 | |
| Others (worsening of preexisting psoriasis) | 1 | ||
| Endocrine disorders | Cushing's syndrome | 1 | |
| Total | 38 | 3 |
Discussion
After an initial very promising case report published in 2005 [34], our study is the first evaluating the efficacy of thalidomide in ACC. In this series of 27 mostly heavily pre-treated patients, we did not observe clinically significant single-agent activity of this drug. Whereas 25 of 27 patients (93 %) experienced clinically or radiolog- ically unequivocal progressive disease at the time of first staging, two patients had stable disease lasting for 25 weeks in one patient.
Over the last few years, systemic therapy for adrenocortical car- cinoma has been intensively investigated. In metastatic disease, mitotane alone or in combination with cytotoxic drugs is consid- ered as a first-line treatment. It has recently been confirmed that objective tumour response can be expected in up to 20% of cases [18]. Cytotoxic chemotherapy is currently regarded as the main- stay of treatment and combination chemotherapy with etoposide, doxorubicin and cisplatin together with mitotane is currently con- sidered as a standard of care according to the first international randomized phase III trial in ACC [19]. Although objective response was observed in 23.2%, progression-free survival is still only 5 months. Other regimens such as gemcitabine/capecitabine [20] result in much lower rates of objective response. Tumour stabiliza- tion is seen in ~25% of patients [21], which is similar to the re- sponse obtained with streptozotocin [19]. Hence, most patients treated with current chemotherapeutic regimes suffer from insuf- ficiently controlled disease and seek additional treatment options.
Extensive neo-angiogenesis as a hallmark of tumour growth has attracted attention also in ACC. Due to the high expression of vas- cular endothelial growth factor (VEGF) and its receptor (VEGFR2) in ACC tumour cell lines [41, 42], prospective phase II clinical trials have been conducted using the multi-tyrosine kinase inhibitors sunitinib and sorafenib [25, 26]. However results were disappoint-
ing and are partly considered to be caused by accelerated metabo- lism of tyrosine kinase inhibitors through induction of cytochrome P450 3A4 by mitotane [43, 44]. It has been argued that thalidomide may be a promising therapeutic alternative for solid tumours since it has both anti-angiogenic and immunomodulatory properties [30-33]. In 2005, the case of a 40-year-old female ACC patient (who experienced a dramatic tumour response to thalidomide) was re- ported [34]. Since then, some centers have used thalidomide as a salvage treatment in selected patients, but efficacy and tolerabil- ity have not been systematically investigated to date.
The present study assessed the efficacy and tolerability of tha- lidomide in patients with refractory ACC. We identified 27 patients who received off-label treatment with thalidomide. Before the lat- ter was initiated, most of the patients had already been treated with several consecutive therapeutic modalities (e. g. surgery, mitotane, cytotoxic chemotherapy, and radiation therapy).
All remaining patients exhibited progressive disease already at the first staging. A possible explanation for this disappointing re- sults in these patients may be secondary drug resistance acquired during previous therapies. However, administering another salvage therapy after various pretreatments is a common circumstance in patients with refractory ACC. Overall, thalidomide treatment was well tolerated but one patient with stable disease declined further treatment after 22.3 weeks due to relatively mild epistaxis and di- arrhea (both CTC grade I).
An obvious limitation of our current evaluation is its retrospec- tive design. This brings along variable clinical management includ- ing restaging at variable time intervals which hampers comparison of treatment effects. Furthermore, the number of cases in our series is still rather small. However, with 27 patients we would expect an initial signal indicating efficacy if present in a clinically relevant pro-
portion of patients and this number is similar to those in phase II clinical trials of ACC (e. g. [26,46]). Moreover, it has to be kept in mind that larger series are difficult to collect due to the rarity of ACC. Another relevant bias of the study is selection bias. As thalid- omide was usually offered only as salvage therapy after failing sev- eral other treatment option, this patient cohort is not representa- tive for all patients with ACC. On one hand, the pre-treatment might have induced - as discussed above - drug resistance, on the other hand, patients, who are still alive after failing these many treatment regimens, have obviously not the most aggressive type of ACC. Stable disease as best response in 2 out of 27 patients (7%) may reflect the natural course of disease.
Absence of response to tyrosine kinase inhibitors in ACC has been previously associated with reduced drug exposure due to strong induction of drug metabolizing cytochrome P450 enzymes by mitotane [43, 44]. Although we did not measure thalidomide plasma concentrations, only minimal hepatic metabolism of this drug has been described which renders this possibility rather un- likely [45]. A single published phase I clinical trials combining lena- lidomide - a related immune modulatory drug (IMiD) - with the mTOR (mammalian target of rapamycin) inhibitor temsirolimus [47] also included three ACC patients of whom one experienced prolonged disease stabilization. It is unclear whether this effect was due to lenalidomide or temsirolimus since a phase II trial of tem- sirolimus with the IGF1-receptor antibody cixutumuab demonstrat- ed stable disease >6months in 11/26 patients. In general, results of “IMiDs” in solid tumours were largely disappointing. Since tha- lidomide was overall well tolerated, one might reason that higher doses of thalidomide may be used in the future. Combination of thalidomide with metronomic chemotherapy such as temozolo- mide [48] or 5-fluorouracil prodrugs [49]might be another option to achieve better tumour response.
In conclusion, our series provide some evidence that thalido- mide has only very modest single-agent activity in patients with refractory advanced ACC. The majority of patients does not bene- fit from the drug. Thus, there is little reason to recommend use of thalidomide as a monotherapy in ACC as long as molecular or clin- ical response markers are yet to be discovered.
Acknowledgments
We are grateful to all the colleagues who provided patient data for the German ACC Registry as well as the ENSAT Registry. We ap- preciate the support for establishing (Uwe Maeder) and maintain- ing (Michaela Haaf) the database of the German Adrenocortical Carcinoma Registry. We are also thankful for the continuous man- agement and technical development of the ENSAT registry by Anthony Stell.
Funding
This research was supported by grants from the Deutsche Forschun- gsgemeinschaft (grant FA 466/4-2 to M.F., KR 4371/1-2 to M.K.), and within the CRC/Transregio 205/1 ,The Adrenal: Central Relay in Health and Disease” (project B16) to M.K. and M.F.
Conflict of Interest
No conflict of interest has been declared by the authors.
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