Radiotherapy in Adrenocortical Carcinoma
Buelent Polat, MD1; Martin Fassnacht, MD2; Leo Pfreundner, MD1; Matthias Guckenberger, MD1; Klaus Bratengeier, MD1; Sarah Johanssen, MD2; Werner Kenn, MD3; Stefanie Hahner, MD2; Bruno Allolio, MD2; and Michael Flentje, MD1
Adrenocortical carcinoma (ACC) is a rare malignancy, and patients with ACC have a poor prognosis. Even af- ter radical surgery, up to 85% of patients develop recurrent disease. Systemic treatment options still have limited efficacy. Because the role of radiotherapy is not defined well and because ACC often is considered radioresistant, the authors reviewed the available data on radiotherapy for ACC. Original articles and reviews were identified using a PubMed search strategy that included the period up to July 2008. Ten articles were identified that covered radiotherapy in a total of 129 patients with ACC (64 patients received postoperative irradiation, and 65 patients received palliative therapy for advanced disease). In addition, 26 patients were identified in the German ACC Registry who received palliative radiotherapy. Furthermore, patterns of failure after adjuvant radiotherapy were investigated, and the authors provided recommendations for patient selec- tion, treatment planning, and treatment protocols. In an adjuvant setting, postoperative radiotherapy was able to prevent local recurrence in the majority of patients. In those with advanced disease, a response to radiotherapy was observed in 57% of patients who received palliative radiotherapy. Therefore, the authors concluded that radiotherapy may play an important role in the care of patients with ACC. Until better evi- dence is available, the authors recommended the following approach: Adjuvant radiotherapy to the tumor bed should be considered in patients at high risk for local recurrence (eg, incomplete/R1 resection); a total dose of >40 grays (Gy) with single fractions of 1.8 Gy to 2 Gy should be administered (including a boost vol- ume to reach from 50 Gy to 60 Gy in individual patients); and radiotherapy in a palliative setting may be used for symptomatic metastases to bone, brain, or vena cava obstruction. With state-of-the-art technology, acute and long-term toxicities mostly were mild to moderate. However, the authors concluded that prospec- tive investigations would be required to fully define the therapeutic potential of this important treatment option. Cancer 2009;115:2816-23. @ 2009 American Cancer Society.
KEY WORDS: radiotherapy, adrenal cancer, adjuvant therapy, palliative therapy, review.
Adrenocortical carcinoma (ACC) is a highly malignant tumor. The 5-year overall survival rate for patients with ACC ranges from 16% to 47%,1-7 and the median survival in patients with advanced disease
Corresponding author: Buelent Polat, MD, Department of Radiation Oncology, University Hospital Wuerzburg, Josef-Schneider-Str.11, 97080 Wuerzburg, Germany; Fax: (011) 49(0)931-201-28221; polat_b@klinik.uni-wuerzburg.de
1Department of Radiation Oncology, University Hospital, University of Wurzburg, Wurzburg, Germany; 2Endocrinology and Diabetes Unit, Depart- ment of Medicine I, University Hospital, University of Wurzburg, Wurzburg, Germany; 3Department of Radiology, University Hospital, University of Wurzburg, Wurzburg, Germany
This study was part of the German Adrenal Network Improving Treatment and Medical Education and the European Network for the Study of Adrenal Tumors. We are grateful to all colleagues who provided clinical data for the German Adrenocortical Carcinoma Registry.
We appreciate the support of Uwe Maeder (Tumor Center, University Hospital Wurzburg) in establishing the German Adrenocortical Carcinoma Registry database and are thankful to Michaela Haaf for documentation. We also thank Dr. Mark Gainey and Dr. Reinhart Sweeney for proofreading the article.
Published online: April 28, 2009 @ 2009 American Cancer Society
DOI: 10.1002/cncr.24331, www.interscience.wiley.com
| Center: Time Frame | No. of Patients | Resection Status | Total Dose, Gy | Response: No. of Patients/Total (%) | Reference/s | |
|---|---|---|---|---|---|---|
| LC | Median Follow-up | |||||
| Yale University, New Haven, Conn:1952-1975 | 4 | R2, spill | 28-41 | 1/4 (25) | — | Percarpio & Knowlton 197619 |
| National Naval Medical Center, Bethesda, Md: 1956-1977 | 4 | R0 | 42-55 | NG | — | King & Lack 197914 |
| Roswell Park Memorial Institute, Buffalo, NY: 1929-1977 | 10 | R2 | NG | 4/10 (40) | — | Didolkar 198136 |
| Mayo Clinic, Rochester, Minn: 1960-1980 | 10 | R0-R2 | NG | 1/10 (10) | — | Henley 198341 |
| Manchester University, Manchester, UK: 1968-1981 | 9 | R0-R2/biopsy | 20-30 | 5/9 (56) | >10 y | Stewart 1974,20 Magee 198715 |
| M. D. Anderson Cancer Center, Houston, Tex: 1944-1987 | 5 | NG | NG | NG | — | Nader 1983,42 Venkatesh 198935 |
| Hahnemann University, Philadelphia, Pa: 1962-1991 | 5 | R0-R2 | 42-60 | 3/5 (60) | — | Markoe 199116 |
| Memorial Sloan-Kettering Cancer Center, New York, NY: 1980-1991 | 3 | R0, R1 | 39-45 | 0/3 (0) | 28 mo | Pommier & Brennan 199210 |
| German ACC Registry, Wurzburg, Germany: 1986-2004* | 14 | R0-RX, spill | 40-54 | 12/14 (86) | 37 mo | Fassnacht 200617 |
Gy indicates grays; LC, local control; R2, macroscopic tumor residue; spill, tumor spillage during surgery; R0, complete resection; NG, not given; R1, micro- scopic tumor residue; ACC, adrenocortical carcinoma; RX, resection status unknown.
*This is the only study that used a group of matched controls. LC was achieved in only 3 of 14 control patients (21%).
(stage IV) is <1 year.8 On the basis of the analysis of 478 patients in the German ACC registry, patient distribution at the time of primary diagnosis according to the newly proposed European Network for the Study of Adrenal Tumors staging system? was 5% for patients with stage I disease, 39% for patients with stage II disease, 27% for patients with stage III disease, and 29% for patients with stage IV disease.7 Thus, the majority of patients initially present with disease that is amenable to surgery. However, even after patients undergo complete surgical resection (R0), both local and distant recurrence is common with recurrence rates of up to 85%,10-12 clearly indicating the need for adjuvant treatment options.
Accordingly, the adrenolytic agent mitotane, which has demonstrated clear antitumor activity in patients with advanced ACC, also has been used in an adjuvant setting with promising results.12 However, even patients who received mitotane had a recurrence rate of approximately 50% within 5 years.13 13
The high rate of local recurrence after surgery with curative intent suggests that adjuvant tumor bed irradia- tion may have significant therapeutic potential by pre- venting the local tumor recurrence that often precedes metastatic tumor spread.5,14-16 This view is supported by a recent study from our group indicating that adjuvant radiotherapy of the tumor bed reduces the rate of local
recurrences.17 In contrast, no beneficial effects of radio- therapy were observed in some earlier investigations, and ACC previously was considered a radioresistant dis- ease. 10,18 In this article, we review the role of radiotherapy in ACC and provide recommendations on the use of radiotherapy based on the literature and on our experience with radiotherapy in patients with ACC.
Previous Experience With Radiotherapy for Adrenocortical Cancer
We searched for all relevant articles in the PubMed and Medline databases that were published after 1960. Key- words used included adrenocortical carcinoma, adrenal cancer, radiotherapy, adjuvant, radiation, treatment, and local recurrence. We identified 10 articles published within the last 30 years that covered a treatment period of almost 80 years (see Tables 1 and 2). In total, 129 patients who received radiotherapy were described, and >50% of them were treated in a palliative setting for metastatic disease.
Sixty-four patients received “adjuvant” irradiation after undergoing surgical resection (Table 1). In most studies, no details on the completeness of resection (R0, R1, or R2) were provided. Furthermore, in most reports, technical details such as the delivered dose or target
| Center: Time Frame | No. of Patients, n=91 | Disease Site | Total Dose, Gy | Indication | No. of Responses/ Total No. | Reference/s |
|---|---|---|---|---|---|---|
| Yale University, New Haven, Conn: 1952-1975 | 7 | Bone, lymph nodes, regional and abdominal recurrence | 15-51 | Pain; intestinal obstruction | 7/7; 2/2 | Percarpio & Knowlton 197619 |
| National Naval Medical Center, Bethesda, Md: 1956-1977 | 12 | Bone, bulky flank tumor | NG | Pain | 6/12 | King & Lack 197914 |
| Mayo Clinic, Rochester, Minn: 1960-1980 | 10 | Irresectable tumor | NG | Pain, large tumor burden | 4/10 | Henley 198341 |
| Manchester University, Manchester, UK: 1968-1981 | 2 | Cervical lymph nodes, lung | NG | Hormone excess; large tumor burden | 1/1; 1/1 | Stewart 1974,20 Magee 1 98715 |
| M. D. Anderson Cancer Center, Houston, Tex: 1944-1987 | 24 | LR or DR | NG | NG | 6/24.v | Nader 1983,42 Venkatesh 198935 |
| Hahnemann University, Philadelphia, Pa: 1962-1991 | 5 | Irresectable tumor or DR; bone, lymph nodes | 30-50 | Pain | 5/5 | Markoe 199116 |
| Memorial Sloan-Kettering Cancer Center, New York, NY: 1980-1991 | 5 | Bone | NG | Pain | 5/5 | Pommier & Brennan 199210 |
| German ACC Registry, Wurzburg, Germany: 1986-2008 | 26 | Bone, LR, abdominal recurrence, lung | 10-60 | Pain (22/26); neurologic (6/26) | 17/22; 3/6 | Current study |
Gy indicates grays; NG, not given; LR, local recurrence; DR, distant recurrence; ACC, adrenocortical carcinoma.
Radiotherapy as palliative treatment of bone metas- tases or extended tumor masses also has been reported. In many patients, good symptomatic control was achieved (see Table 2). However, only limited information on pain reduction, quality-of-life data, and duration of response is
Percarpio and Knowlton described 2 patients who received neoadjuvant radiotherapy at doses from 40 Gy to 45 Gy.19 In 1 patient, the tumor was resected successfully after irradiation, and no local recurrence was observed during follow-up. In the other patient, the tumor also responded to radiotherapy but still was not resectable.
volume definitions were absent. Percarpio and Knowl- ton19 treated 4 patients after incomplete resection with 28 grays (Gy) to 41 Gy at doses of approximately 1 Gy per fraction. After those limited doses, 1 of their 4 patients survived for >11 years without local recurrence. The other patients developed recurrent disease after 2 months, 8 months, and 34 months, respectively. King and Lack reported on adjuvant radiotherapy in 4 patients who sur- vived for >5 years.14 However, those authors did not report whether their patients survived free of disease. Magee et al administered 720 Gy to 30 Gy to the primary tumor site in 9 patients.15 However, they gave no details on disease stage or tumor burden and only concluded that radiotherapy was not effective to control residual bulky disease. Three patients in their report who enjoyed long- term survival had been treated in childhood and had been reported previously in 1974 by Stewart et al after under- going complete surgical resection of the tumor.20 The ar- ticle by Markoe et al16 was the only report that provided technical details on radiation treatment such as field defi- nitions, beam energies, or fractionation. They observed no severe toxicities in 5 patients who were treated adjunc- tive to surgery with a maximum total dose of 60 Gy. Two of those patients had a local recurrence 18 months and 24 months after radiotherapy. One patient developed a local recurrence 31 months after undergoing what appeared to be complete surgery and underwent another surgery that achieved only incomplete resection (R2). Then, she was referred to radiotherapy, received 60 Gy to the residual tu- mor, and had no evidence of disease during follow-up. Pommier and Brennan reported on adjuvant radiotherapy in 3 patients with ACC.10 All 3 of those patients devel- oped recurrent disease after receiving from 39 Gy to 45 Gy, and the authors did not recommend radiotherapy as an adjuvant treatment strategy.
given in the published reports. Most authors recom- mended radiotherapy for palliative treatment, but only Percarpio and Knowlton19 and Markoe et al16 reported on the administered radiation doses, which ranged from 15 Gy to 51 Gy given over 2 weeks to 4 weeks with single fractions of from 1.1 Gy to 2.6 Gy. Response criteria included mainly relief from pain caused by bone metasta- ses or gastrointestinal obstruction. Regression of tumor size or remineralization of ostelytic lesions was not docu- mented regularly. In total, 35 of 65 patients (54%) did respond to palliative radiotherapy treatment.
Experience in Our Institution
We used data from the German ACC Registry (available at: http//www.nebennierenkarzinom.de accessed on April 17, 2009) to conduct a central review of data on adjuvant radiotherapy after macroscopically complete tumor resec- tion.17 No patients had evidence of metastatic disease at the time of radiotherapy, and all were followed for a mini- mum of 12 months. These patients (n = 14) were matched with a control group (n = 14) for resection sta- tus, adjuvant mitotane treatment, disease stage, and tu- mor size derived from the ACC registry. The median follow-up for patients who remained alive (n = 15) was 37 months. Seven of those patients received radiotherapy in our institution (see Table 1).
In addition, we identified 60 patients in the registry who had received radiotherapy in a palliative setting, including 26 patients who had detailed information avail- able on radiotherapy and follow-up (see Table 2). In total, 22 patients were treated for painful osseous metastases, including 6 patients who had additional neurologic symp- toms. Seventeen of 22 patients (77%) described pain relief, and 3 of 6 patients (50%) had a reduction of pares- thesia or paralysis. Eleven patients received higher radia- tion doses for progression of a local recurrence. Taken together with the published data, 52 of 91 patients (57%) had a benefit from radiotherapy. Because of the limited patient numbers, we did not perform further statistical evaluations or subgroup analyses.
Patterns of Failure After Adjuvant Radiotherapy
Because local recurrence in ACC is very common, we ana- lyzed patterns of local recurrence in the 2 patient groups
right
left
Local recurrence
Lymph node recurrence
from our study.17 Figure 1 illustrates the local distribution of right-sided or left-sided recurrence. In the radiation group, 2 of 14 patients (14%) had a locoregional recur- rence on the treated site. In the control group, 11 of 14 patients (79%) developed a local recurrence. The figure illustrates that irradiation of the ipsilateral lymphatic drainage could be insufficient; because, in some patients, interaortocaval lymph nodes were observed. Contralateral lymph nodes have not been observed in our patients during follow-up.
Treatment Concepts for Adjuvant Radiotherapy
We administered daily fractions of 1.8 Gy to 2.0 Gy 5 days per week for 4 weeks to 6 weeks. The total dose ranged a dose between 41.4 Gy and 56 Gy. Eight of 14
| Stage | TNM Classification | R0 | R1 | RX | R2 |
|---|---|---|---|---|---|
| I, II | T1-T2 | * | ++ | ++ | ++ |
| T1-T2 N1 | +* | ++ | ++ | ++ | |
| III | T3-T4 NO-N1} | þ | ++ | ++ | ++ |
| IV | T1-T4 N0-N1 M1 | - | - | - |
R0 indicates complete resection; RX, resection status unknown; R1, micro- scopic tumor residue; R2, macroscopic tumor residue; TNM, tumor, lymph node, metastasis classification; ++, radiotherapy is probably of benefit; +, radiotherapy might be of benefit; - , radiotherapy not recommended.
*Individualized decision (in favor of radiotherapy, microscopic tumor inva- sion of blood vessels and Ki-67 index >10; against radiation, tumor size ≤8 cm).
t Consider undergoing another surgery by expert surgeon.
# Patients with tumor thrombus in the vena cava may not benefit from local radiotherapy.
patients received treatment to a limited boost volume that excluded lymphatic drainage after reaching a dose between 41.4 Gy and 46.6 Gy. In our series, the median planning target volume was 761 mL (range, 236-2127 mL). Several patients were treated by a simple 4 field tech- nique. Wedges were used to obtain a homogeneous dose distribution in the planning target volume.
Recommendations for Practice
The following recommendations are based on personal experience and a review of the literature. Only a limited number of patients have been reported; therefore, the evi- dence level of our recommendations is low. However, in view of the limited treatment options for this rare disease, the potential benefits of radiotherapy should not be neglected. A summary of our treatment recommendations is provided in Tables 3 and 4.
Patient selection for radiotherapy of the tumor bed
We recommend radiotherapy of the tumor bed in all patients who have undergone microscopically incom- plete (R1) resection. In patients who have macroscopically visible residual tumor, a second surgical approach by an expert surgeon should be considered. If this approach is not feasible, then radiotherapy should be performed (in combination with mitotane treatment). Whether this approach has curative potential most likely depends on the remaining tumor volume after surgery. Markoe et al16 reported 1 patient who had long-term survival after radio-
Table 4. Recommendations for Radiotherapy of the Tumor Bed
Radiotherapy should start as soon as possible after surgery (<3 mo) Individualized, CT-based, 3D treatment planning
Individual collimation with MLC; using wedges for dose homogeneity; shielding of the contralateral kidney
Total doses >40 Gy with doses of from 1.8 Gy to 2.0 Gy per fraction Irradiation to a limited boost volume (tumor bed) after at least 40 Gy to reach 50-60 Gy
Concurrent mitotane therapy ≤3 g/d is justified in most patients
CT indicates computed tomography; 3D, 3-dimensional; MLC, multileaf collimator; Gy, grays.
therapy for an incompletely resected local recurrence. Tu- mor regression also was observed in the 2 preoperatively treated patients reported by Percarpio and Knowlton.1 19
An analysis of the German ACC registry indicated that patients who had uncertain resection status (Rx) had a significantly higher risk of recurrence than patients after R0 resection. Therefore, we also consider radiotherapy of the tumor bed for patients with doubts regarding R0 resection status. A third group of patients that may benefit from adjuvant radiotherapy includes patients who have locoregionally advanced disease (especially with invasion to neighboring organs) and/or positive lymph nodes (stage III) with no residual disease after surgery and no evidence of distant metastasis.
In patients with localized tumor and R0 resection, a decision on radiotherapy should be individualized. Cur- rently, we do not recommend adjuvant radiotherapy if the tumor measured ≤8 cm in greatest dimension. Con- versely, we consider radiotherapy for larger tumors that have histopathologic, microscopic evidence of tumor invasion in blood vessels (V1) and a Ki-67 index >10%.
In patients who have intraoperative violation of the tumor capsule, tumor spillage, or dissemination of “necrotic” fluid, there is a high risk of local recurrence. Therefore, these patients may benefit from postoperative radiotherapy. However, if tumor material was spilled throughout the abdominal cavity, then radiation is not indicated. The same most likely is true for patients who have large tumor (thrombus) in the vena cava.
Treatment planning
For treatment planning, a computed tomography- based, individual, 3-dimensional plan should be gener- ated for each patient. Because of the tumor location, it often is unavoidable to expose parts of the kidneys and
liver with higher doses. In these patients, the irradiated partial volume should not exceed the published tolerance doses.21 Shielding of the opposite kidney is important, and analysis of kidney function before treatment is recommended.
Target Definition and Treatment Volume
On the basis of the anatomic distribution of the recur- rences, we derived a clinical target volume, which covered microscopic tumor spread and the lymphatic drainage of the adrenal gland. In agreement with Markoe et al,16 we recommend that the clinical target volume should include the following structures: 1) dorsal, the diaphragm and parts of the thoracic wall in case of infiltration; 2) medial, the para-aortic/paracaval lymph nodes (if involvement was demonstrated or if there is a high risk for this); 3) lateral, as far as the preoperative tumor extension with adequate margins; 4) cranial, up to the diaphragm crus/ apex; and 5) inferior, down to the aortic crest, at least the kidney hilum must be covered. After treating the planning target volume with ≥40 Gy, it is possible to continue irra- diation to a limited boost volume without the lymphatic drainage (if not involved), especially if the target volume includes large parts of critical organs.
Timing for adjuvant radiotherapy
Because the risk of local recurrence is particularly high in the first 2 years after surgery, we recommend start- ing radiotherapy as soon as possible after surgery and not later than 3 months.
Fractionation
The biologic efficacy of radiotherapy in ACC has been investigated recently by Cerquetti et al in a cell culture model.22 Those authors observed a syner- gistic effect of irradiation and simultaneous mitotane treatment.
The highest total dose reported in the literature was 60 Gy at 1.5 Gy to 1.8 Gy per fraction.16 In most studies, lower doses ranging from 20 Gy to 55 Gy were applied. We recommend a standard fractionation scheme with doses from 1.8 Gy to 2.0 Gy per fraction within a treat- ment time of 5 weeks to 6 weeks. Total doses should not fall below a minimum of 40 Gy and should reach 50 Gy to 60 Gy.
Radiotherapy in the palliative setting
Palliative radiotherapy for symptomatic metastatic lesions is a well established and effective treatment option in most cancers. In contrast to some previous publica- tions,10,18 we do not consider ACC a radioresistant tumor (see Tables 1 and 2). Palliative treatment is quite effective as pain relief or for improving neurologic symptoms from metastasis, as described in our own analysis and as reported in the literature. Therefore, palliative radiother- apy should be evaluated on an individualized basis in these patients.
Over the past years, there have been many studies to determine the optimum radiation protocol in patients with bone metastases.23-26 Frequently, short-term fractio- nation schedules, such as single treatment with 8 Gy, were compared with standard treatment of 30 Gy in 10 frac- tions. Most protocols appear to be equally effective in symptom control, but reirradiation was required in a significantly higher proportion when single-fraction treatment was used. An overview on recent studies was provided by Lutz et al.27 Palliative radiotherapy with limited doses also is effective in unresectable abdominal recurrences that cause pain, vascular, or intestinal obstruc- tion. 19 The use of stereotactic radiosurgery may be helpful in the treatment of patients who have good performance status and limited metastases to the brain, lung, or liver. 28-31
It remains an individual decision whether a patient with widespread metastases, symptomatic lesions, and a very limited life expectancy should receive radiotherapy. Clear indications exist for bone metastases with spinal cord compression, superior/inferior vena cava obstruc- tion, and cerebral metastases.32-34
Concomitant treatment
Because new data suggest the use of adjuvant mito- tane after complete resection, the majority of patients scheduled for radiotherapy will receive mitotane. Only 2 studies reported simultaneous treatment with mitotane and radiotherapy.17,35 In our experience, concomitant mitotane may aggravate the adverse effects of radiother- apy. Of concern in this context is liver toxicity (especially in right-sided radiotherapy), and we recommend moni- toring liver enzymes closely. During radiotherapy, we use rather low doses of mitotane (≤3 g per day). Interruption of mitotane treatment rarely is necessary; however, in case
of liver toxicity (increased aspartate and alanine amino- transferase levels ≥3-fold over the individual baseline levels), mitotane has to be stopped immediately to avoid life-threatening liver failure.
There are no data on concurrent radiotherapy treat- ment and cytotoxic chemotherapy. Thus, we do not rec- ommend the concomitant use of cytotoxic drugs outside of clinical trials.
Follow-up and registration of short-term and long-term toxicities
Because of the high recurrence rate, restaging every 3 months is recommended for the first 2 years. After that, restaging intervals may be gradually increased.5
Reported acute toxicitym radiotherapy were only mild to moderate without grade 3 or 4 adverse events. One of our patients developed a partial Budd- Chiari syndrome 3 months after radiotherapy but was free of hepatic symptoms or specific treatment 6 years after treatment.17 Long-term side effects, such as proteinuria or hypertension resulting from kidney impairment, may occur several years after radiotherapy and also require appropriate follow-up. Secondary cancers were reported by Magee et al, who presented 3 patients with long-term survival after radiotherapy and reported the occurrence of osteogenic and soft tissue sarcoma in 2 patients after 11 years and 14 years.15 However, patients with ACC per se have a high incidence of secondary malignancies of approximately 12% to 24%.35,36
Our observation that radiotherapy is tolerated well by patients with ACC is in agreement with published clin- ical studies that considered radiotherapy treatment for ad- renal metastases. Zeng et al37 treated 22 patients who had adrenal gland metastases from hepatocellular carcinoma. With a comparable total dose of 50 Gy, those authors observed only mild acute toxicityommonly nausea and loss of appetite. Impairment of liver or kidney func- tion was not observed during the short follow-up. There are 3 articles on radiation treatment for adrenal metastases from lung cancer. They all state that treatment with even higher doses (up to 60 Gy) generally was tolerated well with only mild gastrointestinal side effects in some patients. 38 38-40
In conclusion, on the basis of studies published over the last decades and our own case series, we conclude that radiotherapy for ACC has significant therapeutic poten-
tial. Adjuvant radiotherapy is able to prevent local recurrence in most patients, although it remains to be demonstrated whether this translates into improved sur- vival. Because of the rarity of the disease, all studies have been retrospective analyses that included only a few patients. However, to reduce the high risk of local recur- rence, we continue to provide radiotherapy to patients who have a high risk of local recurrence after surgery (eg, R1 resection). In addition, radiotherapy is an appropriate palliative treatment option for patients who have sympto- matic bone and brain metastases or vena cava obstruction. Now, prospective trials should be initiated to clarify whether local control can be achieved by radiotherapy, eventually leading to a survival benefit. In the palliative setting, a combined analysis of the increasing number of ACC registries may help to define better the potential of this important treatment option.
Conflict of Interest Disclosures
Supported by grants from the Deutsche Krebshilfe (Grant 107,111 to M.F. and Grant 106 080 to M.F. and B.A.).
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