Prognostic factors for recurrence-free and overall survival after adrenalectomy for metastatic carcinoma: a retrospective cohort pilot study

The adrenal glands are a common site of metastases from a variable primary cancer. Approximately 25% of patients with primary cancer are found at autopsy to have metastases to their adrenal glands [1]. Indeed, it has been estimated that, in patients with a history of a previous malignancy, over 50% of newly discovered adrenal lesions are metastatic [2].

Advances in oncological and surgical therapies have led to a significant increase in the life expectancy of cancer patients and have also prolonged survival of patients with isolated or multiple metastases. Although the overall prognosis for metastatic cancer in the adrenal glands is poor, the survival duration is longer in patients who undergo adrenalectomy for metastatic cancer in comparison to that in patients who undergo resection of metastases in other visceral sites, such as the liver and lung, because adrenal metastasis is often confined within the adrenal gland itself, providing more chances to achieve en bloc removal [3‐6]. It seems reasonable to apply similar criteria for selecting patients for resection of adrenal metastases, including control of extra-adrenal disease, a reasonably long disease-free interval, an acceptable patient performance status, and the absence of significant comorbidity [2]. In this regard, several studies have reported survival benefits of adrenalectomy (ADx) in the setting of metastatic cancer [7, 8] Nevertheless, the prognostic factors for recurrence-free (RFS) and overall survival (OS) after adrenalectomy for metastatic carcinoma are still under debate [8‐11]. Therefore, we evaluated the impacts of clinicopathological variables on the RFS and OS after ADx for metastatic carcinoma in patients with primary cancer.

The adrenal glands are one of the most common sites for metastasis, and the prevalence of isolated adrenal metastasis has increased due to routine surveillance of patients with known malignancy using radiologic examinations based on computed tomography, magnetic resonance imaging, and positron emission tomography [10, 12‐14]. Although small studies related to adrenalectomy in the setting of metastasis have reported improved survival, patients with adrenal metastasis are frequently regarded as inoperable and have a poor prognosis [7, 10, 15]. Prognostic factors and surgical indications for adrenalectomy have not been clearly defined, and more series related to these patients in this setting are needed.

Previously, Muth et al. reported the indication for adrenalectomy for adrenal metastasis with a consecutive series of 30 patients, and the independent prognostic factors of favorable survival were adrenalectomy for potential cure, no previous metastasis surgery, and tumor type [9]. Vazquez et al. identified synchronous disease, tumor type, size, burden, and site as risk factors for poor prognosis in univariate analysis [10]. More recently, Howell et al. suggested that prognostic factors included synchronous disease, a short disease-free interval (DFI), and lung primary [16].

In our study, the independent negative prognostic factors for overall survival (OS) were synchronous metastasis, and GPS. Synchronous metastasis was also an independent prognostic factor in our study. With regard to synchronous metastasis, it was explained theoretically that patients with a tumor presenting as a synchronous metastasis growing faster or more aggressively and patients with metachronous disease could be regarded as having more indolent tumors [16]. With regard to the laparoscopic and open approach, the laparoscopic method could be a feasible option even in aggressive tumor because we believe that our study include the more aggressive tumor [17, 18]. As mentioned before, synchronous tumor and short disease-free interval are related to more aggressive tumor, and overall survival could reflect the tumor aggressiveness [9, 10, 16]. Tanvetyanon et al. reported that the median overall survival was shorter (~12 months) for patients with synchronous tumor [8]. In our study, there were 19 synchronous patients (59.4%), and the disease-free interval was 8.8 months. The median overall survival was only 10.5 months. Muth et al. reported nine patients (30%) with synchronous disease, a median DFI of 26 months, and a median survival of 23 months [9]. Howell et al. described 11 synchronous patients (19%), a DFI > 12 months for 39 patients (81%), and an overall median survival of 30 months [16]. Howell et al. preferred open surgery in patients with multi-focal disease and in patients with more aggressive tumor. In our study, more aggressive patients were included, and the laparoscopic approach could be used in those patients in line with results in previous studies. However, additional studies are needed to clarify this point.

In our study, GPS was selected as an independent poor prognostic factor in multivariate analysis. GPS is based on a combination of CRP and albumin and has been evaluated in a variety of cancers, such as renal cancer, breast cancer, non-small cell lung cancer, gastroesophageal cancer, pancreatic cancer, and colorectal cancer [19‐24]. CRP is a sensitive marker of systemic inflammation, and elevated CRP concentrations are associated with poorer survival in cancer patients, particularly in patients with advanced disease [25]. The association with elevated CRP levels and a dismal prognosis might reflect the prognostic value of tumor produced interleukin-6, an inducer of CRP production in the liver. Presurgical CRP did correlate significantly with shorter RFS and OS in univariate analysis as like other study. Albumin concentrations reflect both systemic inflammation and the amount of lean tissue [25]. GPS, which is a combination of CRP and albumin levels, reflects the effects of systemic inflammatory response and the process of nutritional decline in advanced cancer [26, 27]. However, to our knowledge, there has not been a study to evaluate the prognostic significance in cancer patients with metastatic adrenal lesion. Cancer cachexia and the ECOG performance status have been mentioned as prognostic factors, but ECOG performance status is recognized to be subjective [28, 29]. In our study, GPS had a prognostic value superior to that of ECOG-PS. Mcmillan suggested that the GPS is a simple objective measure that can reflect cancer cachexia and predict outcome in patients with cancer [29]. Furthermore, Lamb et al. reported that an elevated GPS prior to surgery might be a useful prognostic indicator in advanced renal cell carcinoma and may alter the decision for surgery [30]. More research will be needed to validate GPS as a risk factor in cancer patients with adrenal metastasis.

Our study has a number of limitations. The study was hampered by selection bias, and several variables are inter-related because of the retrospective study design. Furthermore, the number of patients was relatively small for multivariate analysis, maybe due to this, there were some discrepancies in the results. Hazard ratio (HR) of both adrenal metastasis was lower than that of single metastasis. Moreover, HR of the presence of previous metastasectomy was lower than no history of previous metastasectomy. In addition, heterogenous tumors are included and malignant potential of primary tumor will be the important factor for OS and RFS. However, the number of each tumor type was not sufficient to assess the prognostic value. Larger cohort study also is needed to find out the prognostic value of the malignant potential of primary tumor.

Finally, our results were expressed with respect to the outcomes of RFS and OS, rather than cancer specific survival (CSS). Future studies of prognostic factors should include CSS as an outcome measure.

In our study, synchronous disease, operation method, and inflammation-based prognostic score were significant prognostic factors for survival associated with adrenalectomy in cancer patients with adrenal metastatic diseases. Synchronous metastasis was also a negative prognostic factor, which is in line with results from a previous study. However, with regard to the operation method, further study is necessary to establish the feasibility of adequate outcomes with a laparoscopic approach in patients with aggressive tumors. GPS appears to be superior to ECOG-PS and could be a simple objective prognostic indicator, but the baseline value of GPS prior to surgery needs to be established in additional studies.