Complete response in a patient with stage IV adrenocortical carcinoma treated with adjuvant trans-catheter arterial chemo-embolization (TACE)
Eugene Wong1,2 İD Sarah Jacques1,2 Michael Bennett1,2 Vineet Gorolay1
Adrian Lee1,2
Stephen Clarke1,2
1 Royal North Shore Hospital, Reserve Road, NSW, Australia
2 Sydney Medical School, University of Sydney, NSW, Australia
Correspondence Eugene Wong, Junior Medical Staff Unit, Royal North Shore Hospital, St Leonards, NSW 2065, Australia. Email: eugene.hl.wong@gmail.com
Abstract
Adrenocortical carcinoma is a rare cancer, with estimate population incidence of 0.7-2.0 cases per 1 million each year. It also carries poor prognosis with estimated 5-year survival of less than 15% of those with metastatic disease and has a poor response to cytotoxic treatment. A randomized controlled trial published in 2012 by Fassnacht et al. demonstrated improved progression-free survival with first-line etoposide-doxirubicin-cisplatin-mitotane (EDP-M) compared to first-line streptozocin-mitotane in patients with stage III-IV disease.
We report a case of a 25-year-old female diagnosed with adrenocortical carcinoma with liver and lung metastases treated with adjuvant EDP-M chemotherapy. During her treatment, the patient experienced ongoing significant liver-associated burden of disease, which prompted a trial of trans-hepatic arterial chemoembolization with doxorubicin and mitomycin. The patient subse- quently experienced complete remission of disease at 18 months with no fludeoxyglucose (FDG) avid lesions on PET/CT.
KEYWORDS
adrenocortical, carcinoma, TACE
1 BACKGROUND
Adrenocortical carcinoma (ACC) is a rare diagnosis, with a popula- tion incidence of approximately 0.7-2.0 cases per 1 million annually.1 Complete surgical excision of the tumor is often considered to be the only avenue for curative treatment, and often requires early diagno- sis with stage I or II disease. Other factors that contribute to success- ful treatment include accurate staging and response to mitotane and chemotherapy.2 Unfortunately, metastatic ACC continues to carry a poor prognosis with estimated survival of less than 15% at 5 years.3 This creates the impetus to try more novel therapies and approaches in this disease.
Trans-catheter arterial chemo-embolization (TACE) is a minimally invasive technique performed by interventional radiologists that deliv- ers chemotherapy with embolization, injected through a catheter, into the hepatic artery directly supplying the tumor. Although TACE is used frequently in hepatocellular carcinoma, neuroendocrine tumors and ocular melanomas, to our knowledge it has only previously been used in one center for ACC.4-6
We present a case of a 25-year-old female who was diagnosed with stage IV ACC with liver and lung metastases. She underwent a left radical nephroadrenalectomy and resection of liver metastases and received etoposide-doxurubicin-cisplatin-mitotane chemother- apy for approximately 6 months. Despite this, she continued to have persistent liver disease progression and therefore underwent TACE therapy. Following this treatment, the patient experienced a complete response to treatment and has remained disease free for more than 30 months up to the latest follow-up.
2 CASE PRESENTATION
A 25-year-old female patient of Vietnamese ethnicity presented ini- tially to her General Practitioner complaining of a six-month history of acne, hirsutism and amenorrhea. She also reported unintentional weight loss of approximately 10 kg over the previous 12-18 months. She had no other relevant past medical history. The patient was a life- long nonsmoker, did not drink alcohol and had no significant family his- tory of malignancy.
The patient was subsequently referred to a Gynecologist and Reproductive Endocrinologist who identified an elevated serum total testosterone level (16 mmol/L) and free androgen index (normal sex hormone binding globulin levels), with a normal pelvic ultrasound.
High-resolution computed tomography (CT) of the chest, abdomen and pelvis subsequently demonstrated a large mass on the left adrenal gland with evidence of local invasion and necrosis. It extended into the right renal vein and inferior vena cava. Additionally, there were liver metastases in segment 8 and 5 of the right lobe, as well as three small pulmonary nodules in the left lower lobe and in the left upper lobe. A CT Pulmonary Angiogram confirmed the above pulmonary findings but also identified the presence of pulmonary emboli and subpleural opac- ities thought to represent pulmonary infarctions.
An FDG/PET scan demonstrated an FDG avid mass in the left adrenal gland with extension into the renal vessels and inferior vena cava. Multiple FDG avid nodes were also identified in both lobes of the liver as well as the pulmonary nodules that were previously identified.
3 TREATMENT
One week after diagnosis, the case was presented in the multidisci- plinary setting with the patient present. In this meeting, there was con- sensus decision made for aggressive primary tumor treatment with anticipation that direct liver therapies may be available later for liver- specific disease.
The patient underwent excision of the left adrenal cortical tumor, left nephrectomy, removal of tumor embolus from the IVC and excision of four liver metastases from segments 4, 5 and 8. The postoperative recovery period was uncomplicated. An FDG PET scan was repeated at 2 months postoperatively (Figure 1).
Pathology of the intraoperative specimen revealed the left adrenal mass as a cortical carcinoma with large areas of necrosis. The nuclei
were equivalent to Fuhrman grade 3, and there was positive stain- ing for inhibin, negative staining for chromogranin and a Ki-67 prolif- eration index of about 25%. The resected liver lesions demonstrated metastatic disease of the same carcinoma.
Following surgery, the patient underwent the first of six cycles of adjuvant EDP-M chemotherapy. The planned and delivered EDP- mitotane regimen consisted of etoposide at a dose of 100 mg/m2 on days 2, 3 and 4 of each cycle; doxorubicin at a dose of 40 mg/m2 on day 1; cisplatin at a dose of 40 mg/m2 on days 3 and 4 and oral mitotane delivered initially at 2 g twice daily then titrated to plasma levels. This was well tolerated, permitting the subsequent five cycles to be administered in an outpatient setting. An FDG/PET scan was then repeated 6 months from initiation of chemotherapy, which displayed complete metabolic response to treatment to the primary lesion and good metabolic response to all pulmonary lesions and most hepatic lesions. However, there was increased FDG avidity in one lesion in seg- ment V of the liver, consistent with disease progression (SUV max = 5.4; previously 4.1).
To address the residual liver metastasis, a trial of liver directed TACE therapy was performed, 4 weeks after the final cycle of EDP-M chemotherapy. Via a right groin puncture, selective superior mesen- teric artery (SMA), right inferior phrenic and celiac contrast injections were performed. Three-dimensional rotational angiography was made on a right hepatic arterial injection, and the area of concern in seg- ment V appeared to be supplied by the right hepatic artery. Doxoru- bicin 20 mg and mitomycin C 10 mg, along with lipiodol and subse- quent gelfoam embolization was made into the right hepatic artery via a micro-catheter. The patient experienced no postprocedural compli- cations and was discharged from hospital the following day.
4 OUTCOME AND FOLLOW-UP
Over the subsequent 2 months, the patient did not undergo any fur- ther cycles of EDP chemotherapy and continued to take Mitotane. An FDG PET scan at this time demonstrated complete metabolic response in the chest and only residual uptake in a segment 6 deposit, which had also improved (SUV max 4.3, previous 5.4).
A subsequent FDG PET scan 2 months later demonstrated com- plete metabolic response with no evidence of FDG avid disease. All subsequent scans have failed to demonstrate FDG avid disease recur- rence, with the latest scan performed approximately 30 months after the date of diagnosis (Figure 2). The patient currently enjoys a premor- bid health-related quality of life with ongoing mitotane therapy.
5 DISCUSSION
Although our understanding in regard to treatments for ACC have improved in recent years, patients diagnosed with metastatic disease continue to experience poor outcomes, with both poorer overall sur- vival and greater burden of disease. Recent data suggest a 5-year overall survival of less than 15% in those with stage IV disease.7 The liver is one of the two most common sites of metastases for ACC and
contributes significantly to the morbidity and mortality of the condi- tion. Liver-directed therapies already demonstrate proven improve- ment in treatment response in other tumors affecting the liver, such as hepatocellular carcinoma, pancreatic neuroendocrine tumors and ocu- lar melanomas. Further research is needed to evaluate the safety and efficacy of liver-directed therapy in ACC.
There is limited evidence regarding liver-directed therapy in the treatment of metastatic ACC. A study conducted by Soga et al, pub- lished in 2009, described two patients with solitary liver metas- tases who underwent transcatheter arterial embolization (without chemotherapy) as well as EDP-mitotane.8 These patients demon- strated a complete response of liver metastases, although they even- tually died from progressive extra-hepatic disease progression.
Another study by Cazejust et al. demonstrated liver morphologi- cal response in six out of 29 patients, and a per-lesion morphological response in 23 lesions out of 102, based on the RECIST criteria.9 In this study, they also demonstrated that lesions that were 3 cm or smaller and those with higher Lipiodol uptake demonstrated a statistically sig- nificant improvement in response rates (P = 0.002 and P < 0.001, respectively). This case differed from our report in that cisplatin was used as the TACE agent in favor of etoposide or doxorubicin. Both Soga and Cazejust’s studies have demonstrated good tumor response, suggesting a greater role of embolization than chemotherapy in liver- directed procedures. Post-embolic syndrome was frequently observed post-procedure, however this was below grade 2 in severity in the majority of cases.
Based on our experience and a review of the limited literature avail- able, liver-directed therapy such as TACE has significant potential as part of treatment protocols in patients who suffer from isolated or sig- nificant liver-associated burden of disease in ACC. We acknowledge that this remains an emerging area, and further research is needed to
guide treatment decisions, particularly as other types of liver directed therapy such as DC beads and SIRT are now gaining popularity. We sug- gest there is a necessity for further higher powered research such as clinical trials into this topic to further clarify the role of TACE in these patients. These concepts also mandate that adrenocortical cancers, like all malignancies, should be managed by a multidisciplinary team that includes endocrinologists, nuclear medicine physicians, endocrine surgeons, medical oncologists and interventional radiologists.
CONFLICT OF INTEREST
There are no conflicts of interest.
ORCID
Eugene Wong ID http://orcid.org/0000-0002-5799-5083
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How to cite this article: Wong E, Jacques S, Bennett M, Gorolay V, Lee A, Clarke S. Complete response in a patient with Stage IV Adrenocortical Carcinoma treated with adjuvant trans-catheter arterial chemo-embolisation (TACE). Asia-Pac J Clin Oncol. 2017;1-3. https://doi.org/10.1111/ajco.12759