Response to radiation therapy in adrenocortical carcinoma
I.G.C. Hermsen1, Y.E. Groenen1, M.W. Dercksen1, J.Theuws2, and H.R. Haak1
1Department of Internal Medicine, Máxima Medical Centre; 2Department of Radiotherapy, Catharina Hospital, Eindhoven, The Netherlands
ABSTRACT. Introduction: Adrenocortical carcinoma (ACC) is a rare disease which is considered resistant to many treatments. The role of radiotherapy in ACC remains unclear. In general ra- diotherapy is thought to be ineffective for the treatment of ACC, and therefore not often used. However, recent reports suggest the opposite. The aim of this study was to perform a retrospective analysis to evaluate the application of radio- therapy in Dutch ACC patients, and to determine the occur- rence of response. Materials and methods: The Dutch ACC Registry (no .= 159) was screened for patients who had re- ceived radiotherapy between 1990 and 2008. Tumor response evaluation was performed according to the Response Evalu- ation Criteria In Solid Tumors (RECIST). Results: Only 13 pa- tients (8% of registered patients) had received radiation ther- apy of whom 6 were irradiated for the palliation of painful
INTRODUCTION
Adrenocortical carcinoma (ACC) is a rare disease which is considered resistant to treatments such as chemother- apy and radiotherapy (1, 2). Treatment is primary sur- gical, with best results described after complete re- section (3). For patients not amendable to surgery, mi- totane remains the treatment of choice. This drug is widely used for the treatment of recurrent and meta- static ACC (4) and may even have a role in adjuvant setting after surgery (5). Mitotane is given alone or in combination with chemotherapy. Currently chemother- apy schedules with streptozotocin (Sz) or etoposide, doxorubicin and cisplatin (EDP) both in combination with mitotane treatment are compared in a large mul- ticenter trial [First International Randomized trial in lo- cally advanced and Metastatic Adrenocortical Carci- noma Treatment (FIRM-ACT), www.firm-act.org]. New developments in the field of angiogenesis blocking and insulin growth factor receptor blocking agents are be- ing studied.
The role of radiation therapy in patients with ACC re- mains unclear. In general radiotherapy is thought to be ineffective for the treatment of ACC, and therefore not often used (2, 6, 7). However, several authors suggest that radiotherapy has significant therapeutic potential (8- 10). Fassnacht et al. even state in a recent review that ACC is not radio-resistant and may be used in adjuvant and palliative setting (11).
bone metastases. In all patients this radiation resulted in pain relief. Three patients received adjuvant tumor bed radiation after resection. Four patients were radiated on irresectable tumor recurrence or tumor metastases. Two patients died soon after radiation therapy and therefore follow-up infor- mation regarding tumor response after radiation therapy of 2 patients was available. Interestingly, partial tumor response according to RECIST criteria, was observed in both patients. Conclusion: ACC can be sensitive to radiotherapy and should be considered in the treatment of advanced ACC, particular- ly in worrisome lesions. The role of radiotherapy in advanced ACC is to complement a systemic treatment such as mitotane or classic cytotoxic agents.
(J. Endocrinol. Invest. 33: 712-714, 2010) @2010, Editrice Kurtis
The aim of this study was to perform a retrospective anal- ysis to evaluate the application of radiotherapy in Dutch ACC patients, and to determine response to radiation therapy.
PATIENTS AND METHODS
The Dutch Adrenal Network Registry (no .= 159) was retrospec- tively screened for patients who had received radiotherapy in the period 1990-2008. Patients were divided in three groups: adjuvant radiotherapy, palliative radiotherapy for bone and/or brain metastasis and radiotherapy for inoperable disease/met- astatic disease.
Tumor response evaluation was performed according to the Re- sponse Evaluation Criteria In Solid Tumors (RECIST) (12). Pa- tients were classified as partial responders if a decrease of at least 30% in longest tumour diameter was seen. In patients re- ceiving palliative radiotherapy for bone metastases, response was defined as pain relief after radiation.
RESULTS
Only 13 patients had received radiation therapy of whom 6 were irradiated for the palliation of painful bone metas- tases. In all patients this radiation resulted in pain relief. Three patients received adjuvant tumor bed radiation af- ter macroscopically complete resection. None of the pa- tients developed local recurrence. In 2 patients distant metastatic disease was observed after 4 and 185 months. One patient is still living 2 years after radiation, without evidence of disease.
Four patients were radiated on irresectable tumor recur- rence or tumor metastasis. Two patients died soon (1 week and 2 weeks, respecively) after radiation therapy and therefore response to therapy could not be deter- mined. Follow-up information regarding tumor response
Key-words: Adrenocortical carcinoma, objective response, radiation therapy.
Correspondence: Ilse Hermsen, MD, Department of Internal Medicine, Máxima Med- ical Centre, PO Box 90052, 5600 PD Eindhoven, The Netherlands.
E-mail: I.hermsen@mmc.nl Accepted December 14, 2009.
First published online March 10, 2010.
after radiation therapy of the other 2 patients was avail- able. Interestingly, tumor response (RECIST) was ob- served in both patients. Because this finding implies that adrenocortical carcinoma is not radio-resistant, these two patients will be described below.
Case 1
In 2003, a 67-yr-old male patient was diagnosed with stage 2 ACC, which was completely resected. At that time no adjuvant therapy was given.
In 2005 the patient presented with recurrent disease. An abdominal computed tomography (CT) scan showed en- larged para-aortal (53 mm) and retrocrural (15 mm) lymph nodes and two small lung lesions (<1 cm). The patient was treated with Sz in combination with mitotane for 2 months. Therapeutic serum levels of mitotane (14-20 mg/l) were not reached. Unfortunately, the treatment was discontinued because of the development of medically induced hepatitis, possibly due to mitotane and/or Sz. No treatment was restarted.
In January 2006, 4 months after discontinuation of mi- totane treatment, the serum level of mitotane was 2.5 mg/l. In May 2006 the slowly growing retrocrural metas- tasis (at that time maximum diameter 63 mm) (Fig. 1) caused back pain. Radiation therapy was given (40 Gy in 16 fractions in 4 weeks), which resulted in a partial re- mission (regression of ≥30% RECIST criteria; maximum diameter 43 mm) (Fig. 1) that lasted 14 months.
Case 2
In 1995, a 52-yr-old female presented with a stage 2 ACC with clinical features of Cushing’s syndrome. A complete
left adrenalectomy was performed. No adjuvant therapy was given.
In 2003, multiple lung metastases were detected on CT scan. Treatment with mitotane was started with an aver- age mitotane level >14 mg/l, which resulted in a partial response of the lung metastases.
In April 2005, progression of the lung metastases was seen despite mitotane levels >14 mg/l. Chemotherapy was initiated first with Sz treatment and later after pro- gression with EDP. After 6 courses of EDP a partial re- sponse was observed.
In May 2006, one pulmonary metastasis situated in the right lower lobe, adjacent to the right hilus, became that large (68 mm) (Fig. 2) that it was considered a direct threat to the mediastinal structures and right lung. In June 2007, the patient received radiation therapy (50 Gy in 25 fractions in 5 weeks), because surgical removal of the lung metastasis was not possible. Follow-up CT scan in Septem- ber 2007 showed a partial remission (45 mm) (Fig. 2) of the pulmonary lesion, which lasted 12 months.
DISCUSSION
The present study confirmed that radiotherapy is not of- ten used in the treatment of ACC. As noted above, only 8% of the registered Dutch ACC patients had received radiotherapy. In the majority of cases radiotherapy was given for painful bone metastases, which lead to pain re- lief in all patients. The application of radiotherapy for ir- resectable disease was even less often used (3%), but re- sulted in partial tumour response in two patients.
Only a few studies are published describing the role of ra-
diation treatment in patients with ACC. Radiotherapy has been described in palliative and adjuvant setting. Ra- diotherapy in patients with bone metastases has proved to be very effective in achieving pain reduction (13), also observed in our group of patients. Unfortunately, the pa- tients did not have follow-up imaging aimed at the as- sessment of morphological changes of the radiated bone metastasis.
Tumor response after radiotherapy has been described in patients with unresectable disease up to more than 50% (14-18). These studies with small number of patients, and often unclearly described methods and response, indi- cate that radiotherapy is effective in this group of patients. That conclusion was also drawn by Allolio et al., in a clin- ical review on ACC, however without giving further evi- dence (8). Our results reinforce this thought, as radio- therapy for irresectable disease resulted in regression of tumor size of more than 30% in 2 patients. Moreover, this response lasted more than one year in both patients.
The role of adjuvant radiotherapy has been studied by Fassnacht et al .. These data suggest that adjuvant tu- mour bed radiation is effective in reducing high rate of lo- cal recurrence, however no significant difference in dis- ease-free and overall survival was found (19). In our group of patients, radiotherapy was effective in preventing lo- cal recurrence. Because of the small amount of patients receiving adjuvant radiotherapy in our cohort, we could not determine impact on survival.
In order to formulate recommendations for the applica- tion of radiotherapy in ACC, three reviews were written (8, 10, 11). All recommend adjuvant therapy in ACC pa- tients with incomplete surgery. In addition to adjuvant therapy they also recommend radiation therapy for bone and brain metastasis or vena cava obstruction. However, no recommendations were formulated for unresectable disease but Fassnacht et al. state in their recent review that ACC is not radio-resistant and radiotherapy may be effective in the treatment of unresectable abdominal or thoracal metastases, without given further evidence (11). We recognize that our study has limitations, because of its retrospective nature and limited number of patients receiving radiotherapy. However, we are the first to ac- curately document patients with tumor response ac- cording to RECIST criteria.
Furthermore, our analysis confirms the therapeutic po- tential of radiotherapy in ACC, and suggests an important role of radiotherapy in palliative treatment of ACC. In summary we conclude that these two cases confirm that adrenocortical carcinoma can be sensitive to radiothera- py and should be considered in the treatment of advanced
ACC, particularly in worrisome lesions. The role of radio- therapy in advanced ACC is to complement a systemic treatment such as mitotane or classic cytotoxic agents.
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