Outcome after resection of Adrenocortical Carcinoma liver metastases: a retrospective study

Adrenocortical Carcinoma (ACC) is a rare malignancy with an annual incidence of 0.7-2.0 cases per million population [ 1] with a poor prognosis [ 2– 4]. Treatment strongly depends on tumour staging classification suggested by the European Network for Study of Adrenal Tumours (ENSAT) [ 5]. Here, primary tumours are classified into four groups (I-IV). ENSAT stage I and II include T1 and T2 primary ACC tumours without lymphatic involvement or distant metastases. Locally advanced tumours or ACC with lymphatic metastases but without distant spread are classified as ENSAT stage III. In these tumour stages, complete resection of primary tumour as well as regional lymphadenectomy with adjuvant mitotane therapy is recommended even if multivisceral resection is required [ 2, 6]. Here, disease-specific 5-year-survival rates of 82%, 61% and 13% for stage I, II and III are reported [ 5].

Metastatic (ENSAT stage IV) and recurrent ACC disease exhibit poor 5-survival rates of less than 15% [ 7]. Nevertheless, if complete resection of distant metastases or recurrent tumour can be achieved, a surgical approach is recommended [ 7, 8] In a series of 154 patients analysed after first recurrence, complete resection of recurrent disease led to a median overall survival of 88 months, when R0 status was achieved, compared to 11 months in cases in whom surgery was not possible [ 9]. Similar results were seen in a recent series from France with 59 patients [ 10]. In the case of metastatic disease of ACC, the liver is one of the most involved organs beside the lung. In contrast to patients with isolated liver metastases (LM) of colorectal origin, in which surgical resection is recommended due to a 5-year overall survival rate of about 42% after first liver resection [ 11], there is as yet only limited data about the value of liver resection for non-colorectal, non-neuroendocrine metastases of other infrequent primary tumours such as ACC [ 12].

In the present study, we report on a retrospective analysis with a high case load using the German Adrenocortical Carcinoma Registry and focusing on a more homogeneous group of patients with resected and non-resected isolated liver metastases without extrahepatic manifestation of ACC origin to proof the value of liver resection for ACC LM.

In this retrospective study, we analysed the benefit of surgical resection of isolated ACC liver metastases based on the German ACC registry. Although the registry contained a substantial number of patients with liver metastases of adrenocortical origin, accounting for 29.7% (306/1031) of registered patients, only 77 of these patients presented with isolated liver metastases and either received surgical resection or systemic therapies alone.

Irrespective of the number of metastases, our analyses demonstrate a very high 5-year survival rate of 51.3% in the 43 liver resected ACC patients. Our data are consistent with previous studies showing similar outcomes after resection of hepatic metastases of ACC origin. In a cohort study of resected non-colorectal and non-neuroendocrine liver metastases of 28 patients with ACC, Adam et al. reported a 5-year overall survival of 66% and a median survival of 63 months after liver resection [ 14]. Based on these data, ACC patients were ranked as the most favourable group for liver resection after non-colorectal and non-neuroendocrine hepatic metastases by these authors. Based on 19 liver patients with metastatic ACC, Ripley et al. reported a 5 year overall survival of 29% after resection, and a 5 year overall survival of 29% patients ( n = 5) that underwent local hepatic thermoablation (RFA) [ 15]. Another case report and review of the literature about thermoablation for ACC LM suggested that RFA should be considered as therapy alternative only for patients in whom resection is contraindicated, due to the increased risk of local recurrence in highly vascularized ACC metastases after ablation [ 16]. Weitz et al. analysed 15 patients with ACC and liver metastases with a 40 months cancer specific survival after resection [ 17]. A subsequent report from the same institution included 28 patients with ACC LM with a disease-free survival of 7 month and a 5 year survival of 39% [ 18]. The latter studies did not exclude patients with extrahepatic tumour manifestation. Thus, the overall outcomes in these studies are reasonably poor compared data obtained from our selected resection group which excluded extrahepatic metastases. Additional data on patients presenting ACC LM suitable for resection but that were never resected is rare or not available in the literature.

Predictive factors to allocate the patient to radical surgery in case of recurrence, seems to be a time to first recurrence (TTFR) of greater than 12 months and a solitary occurrence of liver metastasis. Whereas Erdogan et al. also identified R0 resection as a predictive factor for prolonged overall survival in advanced ACC [ 9], our data did not show a significant difference between R0 and R1 liver resections. A similar effect was shown for colorectal liver metastases, where patients with R1 hepatic resection achieve similar overall survival rates as R0 resected patients, despite a higher recurrence rate [ 19]. This fact could be unique in the case of metastasectomy in the liver. However, we have to acknowledge that the number of our study is too small to prove this hypothesis.

Importantly, however, the results of surgical treatment could not be achieved by nonsurgical therapies alone, such as mitotane or other chemotherapies. For mitotane monotherapy in advanced ACC, distinct data about overall survival in patients without resection is difficult to obtain. Some reports indicate tumour response rates of 13% to 33% [ 20]. However, as recently described in the FIRM-ACT trial, even the combination of mitotane with etoposide, doxorubicin and cisplatin (EDP) resulted in an overall survival of only 14.8 month in advanced ACC [ 21]. In addition, the results of other medical approaches are also of limited or no efficacy [ 22– 27].

Mitotane was shown to have a beneficial effect as adjuvant treatment after radical resection of primary ACC [ 28]. In our study, we did not observe a significant effect of mitotane in the adjuvant/additive setting after resection of ACC liver metastases. Despite the low number of patients, this result might suggest that adjuvant therapy after metastasectomy of ACC by mitotane or chemotherapy does not appear to be very beneficial. Similarly, in a study of 27 patients with synchronously metastatic ACC Dy et al. observed no apparent impact of chemotherapy after metastasectomy on overall survival. Nevertheless, neoadjuvant chemotherapy in the form of mitotane with or without other chemotherapeutic agents like etoposide, doxorubicin and cisplatin was shown to improve overall survival after resection in 8 patients [ 29]. Based on these data, neoadjuvant treatment prior to metastasectomy should be considered as a possible pathway in further drafts of trials for stage IV ACC.

In the group of liver resection, the site of primary ACC was more often on the right side (60%), whereas an equal distribution of the primary ACC to both sides was observed in all 77 patients with isolated liver metastases. Therefore, direct infiltration of the primary tumour into the liver on the right side simulating a solitary metastasis cannot be ruled out for all patients. However, our data suggest that the side of the primary had no significant impact on the overall survival after liver resection (see Table 3). So, the matter of direct tumour infiltration can be neglected.

Reliable information about surgical complications in our study collective could not be obtained from the register. However, by looking at the length of hospital stay and a low in-house mortality it can be assumed that the complication rate of ACC liver metastasectomy is similar to resection of other secondary liver tumours like colorectal liver metastases.

Limitations of the study are its retrospective design and the fact that even after excluding 219 patients with liver metastases and extrahepatic manifestation or with incomplete resection, there are still major differences in the basic characteristics between the two groups of resected and non-resected patients, including median age, diameter of the primary tumour or number of metastases that complicate objective comparison of overall survival.

Yet, due to the rareness of ACC and the fact that a large ACC register was the base for this analysis, larger patient collectives than provided in this study with resected isolated ACC liver metastases and an additional corresponding homogenous control group might be hard to achieve.

Liver resection can achieve long term survival in stage IV ACC with a 5-year survival rate of 51.3% in this study. However, disease-free survival seems to be short as the median disease-free survival is only 9.1 months despite radical metastasectomy. The main predictive factors for improved outcome appear to be the interval between primary tumour manifestation and hepatic recurrence as well as occurrence of a single versus multiple metastases within the liver.