Adjuvant helical IMRT by tomotherapy for bulky adrenocortical carcinoma operated with positive margins: a case report



Adrenocortical carcinoma (ACC) is a rare tumor in the adult. The main therapy is surgery but in some cases radiotherapy may be needed to control the disease locally.


A patient with a surgically removed bulky ACC and pathologic finding of a positive margin was treated at our center by adjuvant mitotane and radiotherapy using an intensity-modulated radiation therapy (IMRT)/image-guided radiotherapy (IGRT) technique by tomotherapy. Dose prescriptions were 63 Gy on the surgical bed and 50.4 Gy on the lymphatic drainage in 28 sessions. Patient compliance was good with no evidence of acute or late toxicities.


Thirty months after radiotherapy, the patient is alive without evidence of disease checked by 18F-fluorodeoxyglucose positron emission tomography/computed tomography and without any complication.


In patients with adverse prognostic features, the delivery of adequate adjuvant radiotherapy doses with IMRT and daily IGRT is feasible and safe and could result in an improved outcome for patients with ACC.

Tumori 2016; 102(Suppl. 2): e96 - e100

Article Type: CASE REPORT



Elena Delmastro, Elisabetta Garibaldi, Domenico Gabriele, Sara Bresciani, Gabriella Cattari, Amalia Di Dia, Claudia Manini, Devis Collura, Maria Grazia Ruo Redda, Pietro Gabriele

Article History


Financial support: None.
Conflict of interest: None.

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Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with an estimated annual incidence of about 2 cases per million people, a poor prognosis, and a 5-year overall survival rate ranging between 16% and 47%. The disease affects women slightly more frequently and has highest incidence in 2 groups of age: childhood and the fourth and fifth decade (1). Regarding clinical presentation, in children about 90% of cases show early symptoms due to adrenal steroid excess with early virilization; conversely, in adults, the disease can be insidious, and its early detection difficult. In women, the disease in 60% of cases presents with progressively worsening Cushing syndrome, and this can lead to hirsutism, male-pattern baldness, voice virilization, and oligomenorrhoea. On the other hand, in male patients or in case of nonsecerning tumors, the diagnosis can be more difficult and can appear with nonspecific abdominal symptoms due to mass effect (1, 2).

Radiologic imaging, such as computed tomography (CT) with contrast or magnetic resonance imaging (MRI) with dynamic gadolinium-enhanced and chemical shift technique, are useful to characterize adrenal lesions. Also, molecular imaging, such as 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET), can be used to address the diagnosis towards a malignant nature, giving more information on the staging of the disease, which in about 33% of cases presents at diagnosis with distant metastasis, more frequent in lung and liver (2).

Surgery is the milestone in localized and operable ACC, with the goal of obtaining negative margins to provide a greater chance of cure (3). Adjuvant therapy is recommended in almost all patients since, even in completely resected cases, the relapse risk remains high (60% to 80%) (4-5-6). Even more, an adjuvant treatment is mandatory if surgery is not microscopically radical and a second surgery is not feasible. Several studies show that adjuvant mitotane can potentially prolong the disease-free and overall survival (4). If positive margins occur, as well as in patients with not assessed margins, advanced locoregional disease (stage III), or likely aggressive tumors (e.g., Ki67 >10%), adjuvant radiotherapy to the tumor bed should be considered (5, 6). Radiotherapy dose delivery can be difficult using conventional techniques, due to the necessity to set up high doses on the tumor bed closed to several adjacent radiosensible organs (i.e., kidneys, spinal cord, liver, small bowel, stomach, and pancreas). However, recent technological advances, in particular the spread of highly conformal techniques like intensity-modulated radiation therapy (IMRT), could help to overcome this problem, allowing a dose escalation also in intra-abdominal sites. Furthermore, the association with image-guided radiotherapy (IGRT), as with tomotherapy, can allow a daily check of patient setup and target position, in order to obtain a precise and safer treatment.

We report a case of a patient with a surgically removed ACC treated by adjuvant mitotane and radiotherapy using an IMRT-IGRT technique by tomotherapy.

Case report

A 38-year-old man with a surgically excised ACC was referred for the first time to our center in January 2012. In August 2011, he had 2 episodes of intermittent fever, with spontaneous resolution. At the same time, he reported a slight weight loss (5 Kg within 1 year) and moderate anorexia. Abdominal ultrasound showed the presence of a left retroperitoneal mass, with a diameter of about 20 cm. The CT scan confirmed the finding (Fig. 1). The lesion showed an expansive growth without evidence of infiltration in surrounding organs, which appeared displaced but not infiltrated. In November 2011, the patient underwent laparoscopic surgery with left adrenalectomy, splenectomy, and para-aortic lymphadenectomy. Definitive pathologic finding showed an ACC with low nuclear grade and low proliferative index (Ki67 3%), but with vascular invasion and extensive areas of necrosis, positive to calretinin (Fig. 2); the retroperitoneal resection margin was focally positive (R1); metastases were not found in the lymph nodes or in the spleen. Hence, the postoperative stage was pT2 pN0 R1. After that, the patient underwent postoperative restaging consisting of CT, MRI, and FDG-PET-CT, all examinations being negative. In January 2012, the patient began adjuvant mitotane and was evaluated for adjuvant radiotherapy, due to the positive surgical margin.

Preoperative computed tomography scan shows the 20-cm retroperitoneal mass.

Pathologic findings of the adrenocortical carcinoma: a) EE-20x; b) necrotic areas; c) immunohistochemistry positive to calretinin; d) macroscopic sample.

The patient was scheduled for IMRT by linear accelerator (LINAC) (54 Gy in 2-Gy fractions, 9-fields step-and-shoot technique) but the planning was judged not respectful of the constraints to the neighboring organs at risk, particularly the kidney. Therefore, the patient was sent to our Radiotherapy Division where, between February and March 2012, he received adjuvant radiotherapy by IMRT technique with simultaneous integrated boost and daily IGRT, using tomotherapy Hi-Art system (Tomotherapy Inc., Madison, Wisconsin, USA).

The volumes and prescription doses were as follows:

Clinical target volume 1, including retroperitoneal positive margin (as marked by surgical clips) and adjacent aorta with a margin of 3 mm (Fig. 3), to obtain planning target volume 1 (PTV1); dose prescription was 63 Gy in 28 fractions, with 2.25 Gy per fraction and 5 days per week for 6 weeks; fusion of presurgery and postsurgery imaging was not performed because of the wide deformation of the tumor on neighboring organs, which hampered any reliable comparison

Clinical target volume 2, including the retroperitoneal surgical bed and the regional lymphatic drainage, consisting of the lumbar-aortic lymph nodes between the 10th thoracic intervertebral space and the 2nd lumbar intervertebral space; a margin of 5 mm was added to obtain planning target volume 2 (PTV2); dose prescription was 50.4 Gy/28 fractions, with 1.8 Gy per fraction and 5 days per week for 6 weeks

Postoperative planning computed tomography (with surgical clips).

For both volumes (PTV1 and PTV2), the dose was prescribed to 95% of the PTV (D95%) (Fig. 4). All organs at risk (OAR) were contoured: kidneys, small bowel (defined as intestinal cavity), liver, spinal cord, stomach, pancreas, and heart. The treatment planning evaluation was performed according to International Commission on Radiation Units & Measurements (7) and Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) recommendations (8). Daily megavoltage computed tomography imaging (MVCT) was performed to verify treatment reproducibility.

Graphic representation of treatment planning with dose distribution (in colorwash) on the surgical bed (63 Gy) and on the prophylactic lumbar-aortic lymph nodes (50.4 Gy).

In order to evaluate tolerance and acute toxicity, the ­patient was submitted to overall physical evaluation and laboratory tests (blood counts, renal, liver, and pancreatic functions). During radiation treatment, he was examined every week and laboratory tests were repeated every 3 weeks. Acute and late toxicities were evaluated according to Radiation Therapy ­Oncology Group toxicity scales (9) and laboratory test results, and the outcome by physical examination, MRI, and FDG-PET-CT scans.

Patient compliance was good and no treatment interruptions were required due to collateral effects. The time of ­irradiation was 8 minutes and the average time for MVCT acquisition 2.5 minutes; the overall treatment field was 16.5 cm long. The mean doses to PTV1 and PTV2 were 64.0 Gy and 51.4 Gy, respectively. The constraints to the OAR, evaluated using dose-volume histograms, were always lower than QUANTEC recommendations (Tab. I). Acute gastrointestinal toxicity was G2, with nausea requiring medication. During and after radiotherapy, the patient continued mitotane: adjuvant mitotane was performed for 18 months overall.

Mean and maximum doses at organs at risk and target volumes

OAR D mean, Gy D max, Gy
OAR = organs at risk; PTV = planning target volume.
Pancreas 46.8 65.2
Stomach 26.8 52.4
Liver 15.9 48.7
Right kidney 8.5 20.6
Left kidney 16.7 45.2
 PTV-1 (Boost) 64.0 67.4
 PTV-2 51.4 62.2

Thirty months after radiotherapy, the patient was alive without evidence of disease checked by FDG-PET-CT. Blood cell counts were slightly altered due to mitotane therapy, but hematologic toxicity was G0. Renal and hepatic functions were normal and no late toxicity has been reported.


The prognosis of ACC is poor despite radical surgery, with a recurrence risk up to 80% (1, 2). Adjuvant radiotherapy may reduce this risk, but its role remains to be defined. Literature data about irradiation of ACC are controversial and lacking.

A review article, published in 2009 by Polat et al (5), showed that since the 1970s there were only 10 articles published, over a follow-up period of almost 80 years. A total of 129 patients received radiotherapy, over 50% of whom were treated in a palliative setting for metastatic disease. Sixty-four patients received adjuvant radiotherapy after surgical resection, but in most studies there was no information about the margin status nor technical details about radiotherapy. In between the quoted studies, only Markoe et al (10) reported information about field conformation, beam energies, and fractionation; they observed no severe toxicities in 5 patients treated by adjuvant radiotherapy with a total dose up to 60 Gy. Polat and colleagues (5, 6) reported a loco-regional recurrence rate of 14% in the group of irradiated patients (with dose range between 42 and 56 Gy by conventional fractionation) versus 79% in the control group, concluding that radiotherapy may play a significant role in the care of patients with ACC.

In 2011, Sabolch and colleagues (11) reported 26 patients treated by radiotherapy. Of these, 10 received adjuvant radiotherapy with a median dose of 53.4 Gy (range 45-57 Gy), while the other 16 received definitive radiotherapy for unresectable disease, with a median dose of 39.2 Gy (range 22.5-73.5 Gy). Radiotherapy was performed by 3D conformal radiation therapy or IMRT technique in 25 patients and one patient received interstitial brachytherapy. The authors reported a local recurrence in 16 of 48 patients treated by surgery alone versus 2 of the 10 treated with adjuvant radiotherapy versus 1 of 16 treated by definitive radiotherapy; acute toxicity was graded ≥2 in 50% of the 26 patients receiving radiotherapy (mainly nausea and/or emesis). They conclude that definitive radiotherapy can be an effective treatment in unresectable disease and strongly advise considering adjuvant radiotherapy after surgical resection.

The MD Anderson Cancer Center experience, carried out between 1998 and 2011 and published in 2013 by Habra et al (12), reported a local recurrence of 43.8% in 16 patients treated with adjuvant radiotherapy versus 31.3% in 32 patients treated by surgery alone. Doses in the radiotherapy group ranged between 36 and 59.4 Gy (with median dose 50.4 Gy): the authors concluded that radiotherapy did not improve outcome and suggest the need for a multicenter prospective randomized trial to evaluate the role of adjuvant treatments.

On the other hand, the German ACC consortium (5) recommends adjuvant radiotherapy in patients with microscopically positive or uncertain margins and in those with stage III disease. Moreover, radiotherapy is to be considered in patients with microscopically complete resection but with risk factors (tumor size >8 cm, vascular invasion, Ki67 index >10%). A standard fractionation (1.8-2 Gy per fraction) and total doses not less than 40 Gy (preferably between 50 and 60 Gy) are recommended.

The delivery of these recommended doses in abdominal sites can be difficult using conventional external beam techniques and, currently, no studies are reported about new advanced radiotherapy techniques like IMRT-IGRT. In fact, IMRT can allow a good dose conformation, suitable for irregular or concave targets. It can be performed with LINAC or dedicated equipment, such as helical tomotherapy, which allows IMRT with helical modality. Furthermore, tomotherapy permits, by the included onboard CT module, the daily acquisition of volumetric images of the patient setup immediately before the treatment session. These images are compared with those of treatment planning to directly visualize soft tissues (such as liver, kidneys, lungs, intestinal cavity) in addition to the bony landmarks, allowing a daily IGRT to verify the treatment exactness and focalize the dose on the target with higher precision and safety. Therefore, with tomotherapy the irradiation of complex, irregular volumes is feasible even in close proximity to OAR, without sacrificing dose escalation.

In our patient, we were able to administer an escalated dose of 63 Gy with simultaneous boost in the region at the highest recurrence risk, using a moderate hypofractionation schedule (2.25 Gy per fraction) and with an excellent sparing of nearby OAR. Treatment was well-tolerated, no severe acute or late toxicities were observed, and the patient had no evidence of disease at 30-month follow-up.

The delivery of adequate doses is feasible and safe with IMRT and daily IGRT by tomotherapy and could result in an improved outcome for patients with ACC. Owing to the rarity of ACC and the complexity of this kind of radiotherapy, patients should be treated in a multidisciplinary context and the availability of a modern radiotherapy device should be recommended. Multicentric randomized prospective trials including IMRT techniques and the possibility of concomitant IGRT are strongly advised to define the role of adjuvant radiotherapy in these patients.


The authors thank the program 5 x Mille, 2008, Ministero della Salute-FPRC onlus.


Financial support: None.
Conflict of interest: None.
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  • Radiotherapy Division of the FPO-IRCCS Cancer Center, Candiolo (Turin) - Italy
  • Neuroscience Department, Human Physiology Section, University of Turin, Turin - Italy
  • Medical Physics Division of the FPO-IRCCS Cancer Center, Candiolo (Turin) - Italy
  • Pathology Division of the San Giovanni Bosco Hospital, Turin - Italy
  • Urology Division of the San Giovanni Bosco Hospital, Turin - Italy
  • Radiotherapy Unit, S. Luigi Hospital, Orbassano, University of Turin, Turin - Italy

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