© 2005 Foundation for Promotion of Cancer Research
Radiation Therapy for Adrenal Gland Metastases from Hepatocellular Carcinoma
1 Department of Radiation Oncology, 2 Liver Cancer Institute, 3 Department of Radiology and 4 Department of Clinical Laboratory, Zhongshan Hospital, Fudan University, Shanghai, China
For reprints and all correspondence: Zhao-Chong Zeng, Chairperson, Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China. E-mail: zczeng{at}zshospital.net
Received August 22, 2004; accepted December 4, 2004
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Abstract |
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Background: The adrenal gland is a common site of extrahepatic metastases from hepatocellular carcinoma. However, it has been the subject of few studies, and the optimal treatment remains unclear. Methods previously tried for the management of adrenal gland metastasis of hepatocellular carcinoma included surgical resection, transarterial chemoembolization or percutaneous ethanol injection, on the basis of case reports. External beam radiation therapy has seldom been applied for patients with adrenal gland metastases.
Methods: We retrospectively studied 22 patients with adrenal metastases from hepatocellular carcinoma who were treated with limited-field external beam radiation therapy. The radiation dose to the adrenal lesion ranged from 36 to 54 (median 50) Gy, while the intrahepatic lesions were treated with either surgical resection or transarterial chemoembolization.
Results: Among the 14 patients who had pain related to adrenal metastases, 11 (78.6%) had complete pain relief without medication that lasted until death. Two (14.3%) patients had marked pain relief, but still required analgesics. Partial responses were observed in 73% of the patients. The median survival period for all patients was 10 months. No patient died from complications related to adrenal metastasis. Adverse effects were mild.
Conclusion: Adrenal metastases from hepatocellular carcinoma are sensitive to radiation treatment. Radiation therapy with 50 Gy for adrenal gland metastases is a good palliative therapy with reasonable safety.
Key Words: hepatocellular carcinoma • external beam radiation therapy • adrenal metastasis • survival
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Adrenal glands are the second most frequent site of metastasis from hepatocellular carcinoma (HCC), being found in 8% of autopsies (1,2). However, adrenal gland metastases have been the subject of only a few studies, and their optimal treatment remains unclear. Various methods have been tried to manage this condition including: surgical resection (3,4), transarterial chemoembolization (TACE) (5), percutaneous ethanol injection (6) and external beam radiation therapy (EBRT) (7), as case reports. Many patients have been demonstrated to benefit from surgical resection of adrenal metastases, and long-term survival can be achieved (4). Unfortunately, the discovery of an adrenal metastasis in patients with primary tumor automatically transfers them to an advanced stage. In such cases, surgical resection is not usually considered due to the unresectable intrahepatic tumors, tumor thrombi, lymph node involvement and synchronous distant metastases to bones or lungs. The effect of TACE on the adrenal metastases theoretically should be good, because metastatic lesions are hypervascular like primary HCC. However, TACE would not actually be performed, as catheterization to the adrenal arteries and complete embolization of the adrenal gland are anatomically difficult (Fig. 1). Percutaneous ethanol injection may be useful for small lesions, but is not sufficiently effective for a larger tumor. In the present study, we retrospectively studied the effects of radiation on adrenal gland metastases from HCC.
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PATIENTS AND METHODS |
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PATIENTS
We conducted a retrospective review of 22 HCC patients with adrenal gland metastasis diagnosed and treated at our hospital from January 2000 to April 2004. The median period from initial therapy for the primary tumors (surgical resection or TACE) to EBRT for adrenal gland metastases was 6 months [95% confidence interval (CI) 0.25–11.75]. The patient characteristics are listed in Table 1.
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Of the 22 patients identified, the diagnosis of HCC was confirmed by histology (surgical specimen) in 13 patients (59.1%); a typical clinical presentation and serum
-fetoprotein (AFP) 
400 µg/l in five patients (22.7%); and unequivocal clinical and radiological findings in one patient (4.6%) whose AFP was 
400 µg/l and in three patients (13.6%) whose AFP was negative (20 µg/l). A variety of modalities available for imaging HCC (8–10), such as computed tomography (CT) scan, ultrasonography, magnetic resonance imaging (MRI) and hepatic angiography, were used in this study.
For clinical diagnosis, the patients had to meet the following criteria issued by the Chinese Liver Cancer Association in 1999 (11). First, the AFP level should be 400 µg/l, to rule out patients with active liver disease, embryonal malignant teratoblastomas of the testes or ovary, or other malignant tumors metastasizing to the liver, and the tumor should have a characteristic appearance on one of the HCC imaging methods listed above. Secondly, if the AFP level is <400 µg/l, the characteristic intrahepatic lesion should be confirmed by two of the HCC imaging methods listed above. To exclude patients with metastatic tumors from the digestive system or intrahepatic cholangiocarcinoma, the status of carcinoembryonic antigen or carbohydrate antigen 19.9 (CA19.9) should be negative for those with negative AFP levels.
In this study, the adrenal gland metastases from HCC were confirmed by laparotomy in five patients, and by angiography in six patients during TACE. The remaining 11 patients were diagnosed as having adrenal gland metastasis based on the CT finding. Helical CT with 6.5 mm cuts confirmed the presence of adrenal lesions. The adrenal lesions have a characteristic angiographic appearance, with hypervascularity supplied mainly by the adrenal arteries (Fig. 1). Angiography is useful in identifying feeding arteries and in defining the tumor origin, so that we can differentiate the adrenal gland metastases from the intrahepatic tumors invading the right adrenal gland metastasis. The Karnofsky performance status score was >90 in all patients.
THERAPIES
Written or oral informed consent regarding treatment course was obtained from each patient in a standard procedure at each department. Intrahepatic primary tumors were treated with TACE alone in 12 patients and with resection in 10 patients. Surgical resection focused on the removal of only the intrahepatic primary tumors. TACE comprised a combination of targeting chemotherapy with 1 g of 5-fluorouracil (5-FU), 80 mg of cisplatin (DDP), 10 mg of mitomycin C (MMC), and arterial embolization with 10 ml of iodized oil (Lipiodol Ultra Fluid, Lab. André Guerbet, Aulnay-sous-Bois, France) mixed with 10 mg MMC that has both a selective ischemic and a chemotherapeutic effect on intrahepatic primary tumors.
Patients received limited-field EBRT using a linear accelerator with a 6 or 15 MV (depending on tumor location and depth) photon beam strictly focused on the adrenal lesion. At initial simulation, patients are immobilized while supine in custom-made cradle molds which are used for all phases of planning and therapy. The patient's arms are folded behind the head to allow the use of oblique treatments from any angle. Because the adrenal gland is located in the retroperitoneum, the lesion is seldom affected by respiratory motion. If the adrenal metastatic lesion was larger (as in case 14) and close to the liver, the patients received training in respiration to reduce the amplitude, increase the frequency and minimize tumor movement before the initiation of EBRT. The respiratory movement was estimated during simulation, and if it was >1.0 cm, pressure was applied to the patient's abdomen with the goal of minimizing the movement. CT scan slices are obtained at intervals of 6.5 mm from the superior to the inferior extent of the simulated fields. The gross disease target volume is outlined by placing a 1 cm margin around the radiographically visible adrenal lesion. Two posterior oblique fields are used. Wedges were used to alter the dose distribution in a beam. Two beams were separated by 90° and with 45° wedges in a SAD (source-to-axial distance) technique. This combination of fields allows sparing of the liver, the spinal cord, bowel intestines and the opposed kidney. Figure 2 shows the dose distribution resulting from delivering 50 Gy via posterior oblique fields with 45° wedges. The square of radiation fields was usually <100 cm2. The median tumor dose was 50 Gy (range, 36–54 Gy) in daily 2.0 Gy fractions, five times a week. We scheduled the full radiation dosage up to 50 Gy, but some factors were taken into account that indicated the need for a reduced dose, such as adverse effects, the status of intrahepatic tumors and distant metastasis during EBRT. A radiation dosage <40 Gy was delivered in one patient because of the distant metastasis during EBRT. The dose was between 40 and <50 Gy in six patients and between 50 and 54 Gy in 15 patients. Depending on the field size and anatomic location, all or part of the right kidney was in the radiation fields. In such cases, an initial left renal evaluation with intravenous pyelography was performed to ensure that the left kidney had adequate function.
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In this study, one patient had bilateral adrenal metastases. We designed radiation fields with anterior and posterior parallel ports in each side, and reduced the radiation dose to 40 Gy. For the patients with synchronous extrahepatic metastases, we concurrently treated both adrenal and extrahepatic lesions with EBRT.
ASSESSMENT OF RESPONSE AND TOXICITY
Pre-treatment evaluation included a medical history and physical examination, complete blood cell count, serum chemistries (including creatinine, blood urea nitrogen and urinary acid), liver function tests, 
-glutamyltransferase, AFP for those who tested positive at the initial evaluation, chest X-ray, abdominal ultrasonography and enhanced CT or MRI. Clinical monitoring was performed once a week. Hepatic angiography was obtained in patients who received TACE.
FOLLOW-UP
Patients were advised about the need for regular follow-up 6 weeks after the completion of EBRT. Patients were monitored with abdominal enhanced CT scan or MRI in the first follow-up, and then were monitored every 3 months thereafter. Tumor response was compared with two investigations 
3 months apart, from pre-EBRT to the first follow-up. A complete response (CR) was defined as the complete disappearance of all clinical and radiographic evidence of the tumor. A partial response (PR) required a 50% reduction in the sum of the products of the longest diameter and its perpendicular on the CT scan or MRI. Stable disease (SD) indicated a decrease of <50% or an increase of <25% in the product of the longest perpendicular diameters of measurable tumor. Progressive disease (PD) was defined as an increase of 25% in the sum of the products of the longest diameter and its perpendicular, compared with the lowest value recorded, or as death from HCC within 3 months. Objective response was calculated for CR and PR; no response was calculated for SD or PD.
Serum AFP level was determined using the electrochemiluminescence immunoassay from Roche Diagnostics Corporation. For patients who were positive for AFP, the serum AFP was assayed in the first follow-up. AFP changes were compared with two investigations 3 months apart, from pre-EBRT to 6 weeks after completion of EBRT. AFP decline required a value <20 µg/l or a 10% reduction.
The overall survival period was defined as the period from the date of diagnosis of adrenal metastases to the date of death or the last follow-up appointment. Cumulative survival rates were analyzed by Kaplan–Meier plots.
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RESULTS |
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RESPONSE TO EBRT
Symptoms included pain in the back/flank in nine patients, and epigastric or upper quadrant visceral pain in five patients. One patient presented edema of the lower extremities, which was caused by the compression of the inferior vena cava (case 14). Patients were scored as having achieved a CR in 11 cases who had complete pain relief without medication that lasted until death; a good response in two patients, who were defined as having marked pain relief that still required analgesics; and no response in one patient due to synchronizing lymph node involvement (case 7). The patient who presented edema of the lower extremities had complete relief.
Of the 22 patients with adrenal gland metastases who received EBRT, 16 (73%) achieved a PR on their adrenal lesions. During follow-up, two patients showed adrenal lesion relapse 1 year after completion of EBRT; however, their intrahepatic tumors were controlled well. These two patients received the second course of EBRT with 40 Gy on the same fields, and PR was again obtained. Figures 3 and 4 illustrate the typical cases of adrenal involvement. When comparing abdominal CT scans between pre- and post-EBRT, the metastatic lesions showed marked shrinkage.
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SURVIVAL AND FAILURE PATTERNS
At the time of analysis, four patients were alive and 18 had died. The median survival period for all patients was 10 months. The survival rate at 1 year of patients treated with EBRT was 42.5%, as shown in the survival curve (Fig. 5).
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No patient died from adrenal metastasis-related complications. Death usually resulted from liver failure caused by tumor progression. The causes of death were liver failure in 15 patients (83.3%), pulmonary metastases in two patients (11.1%) and lymph node involvement in one patient (4.6%).
ADVERSE EFFECTS
The most common adverse effects of EBRT were loss of appetite and nausea during the procedure. They usually occurred at the end of EBRT, and patients did not need fluid infusion. None of these adverse effects affected the timing and delivery of EBRT. There was no deterioration of liver function during EBRT. No clinical symptoms of radiation-induced nephritis (hypertension, anemia, elevated blood urea nitrogen and creatine levels or albuminuria) were observed during and after EBRT. No patient had duodenum and small bowel bleeding. No patient was found to have a leukocyte count <2 x 109/l. Three patients had survived >2 years after EBRT; no long-term treatment-related morbidity was identified.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Metastatic tumor is the most common lesion in the adrenal gland at autopsy, which is related to its rich sinusoidal blood supply. Theoretically, metastases should involve the right and left adrenal glands with equal frequency. However, we observed a striking disparity in favor of the right adrenal gland (19 out of 22). This result is similar to the report by Momoi et al., in which the metastatic probability in the right side was 13 out of 20 (4). The reasons for these results are not known.
It has generally been thought that patients with HCC have a relatively low incidence of distant metastases compared with the rather frequent intrahepatic occurrence. However, advances in diagnostic and treatment modalities have enhanced the possibility of long-term survival for patients with this disease, and increased the clinical significance of distant metastases. Symptomatic disease occurs less often than in other common areas of metastases; however, when manifested clinically, there are few treatment options which have proven effective to be found in the published data.
Of 22 patients with adrenal metastases, 15 (68.2%) visited doctors because they suffered from clinical symptoms related to the adrenal metastases. Most of them (14 out of 15) had a good response with relieved symptoms. The tumor response rate was as high as 73% after EBRT. The results reflect the fact that adrenal metastasis from HCC is sensitive to EBRT. The lack of control of the intrahepatic lesions remains the major problem. Death from adrenal gland metastasis was not recorded in the patients who received EBRT. Thus, it is important to treat the intrahepatic lesions appropriately after EBRT for adrenal lesions.
The incidence of adrenal gland metastases in HCC patients is much higher in the autopsy series than that expected from the clinical data. This means that adrenal gland metastases usually do not result in the death of HCC patients. Even though the metastatic lesions disappeared after EBRT, it is difficult to answer the question as to whether EBRT really improved the survival of these patients. In this regard, we could compare the present results with the recent report from Japan that the median survival is 306 days in HCC patients with adrenal metastases who received either adrenalectomy, TACE or percutaneous ethanol injection (4). It seems that EBRT is effective in the adrenal metastases from HCC, at least equal to adrenalectomy reported in the literature.
Radiation therapy in previously irradiated patients must be undertaken with extreme caution. It is very important to analyze the techniques used in the initial treatment (beam energy, volume and dose delivered with external irradiation). Also, the period of time between the two treatments must be taken into consideration because it is postulated that some repair of the initial damage may take place in the interval. In this study, EBRT for recurrent adrenal tumor was given in limited volumes (40 Gy; 2 Gy daily fraction) in two patients. Higher doses may be associated with a higher incidence of morbidity; however, we note no incidence of bowel, kidney or liver sequelae in these two patients. This suggested that radiation doses might be increased. We will try to deliver 60 Gy to adrenal lesions for those patients who had been well controlled for intrahepatic tumors. This is due to the existence of less normal tissues (bowel or liver) around the designed fields. Lateral fields are not appropriate for adrenal tumors. This again emphasizes the importance of careful treatment planning to avoid injuries to the opposing kidney. Also, clinical manifestations of renal irradiation are now unusual because of our increased awareness of the marked radiation sensitivity of this organ and subsequent care in treatment planning.
In conclusion, adrenal metastases from HCC are sensitive to radiation treatment. EBRT for adrenal gland metastases is a good palliative therapy with reasonable safety. The need for a further large-scale study appears to be warranted to compare the treatment results with and without EBRT.
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Acknowledgments |
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This study was supported by a grant from the Key Center of Hepatoma of Shanghai Municipal Clinical Medicine.
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References |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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