Pooled analysis for surgical treatment for isolated adrenal metastasis and non-small cell lung cancer

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1 Interactive CardioVascular and Thoracic Surgery 24 (2017) 1 7 doi: /icvts/ivw321 Advance Access publication 23 September 2016 ORIGINAL ARTICLE Cite this article as: Gao X-L, Zhang K-W, Tang M-B, Zhang K-J, Fang L-N, Liu W. Pooled analysis for surgical treatment for isolated adrenal metastasis and non-small cell lung cancer. Interact CardioVasc Thorac Surg 2017;24:1 7. Pooled analysis for surgical treatment for isolated adrenal metastasis and non-small cell lung cancer Xin-Liang Gao, Ke-Wei Zhang, Ming-Bo Tang, Ke-Jian Zhang, Li-Nan Fang and Wei Liu* THORACIC Department of Thoracic Surgery, First Hospital of Jilin University, Changchun, China * Corresponding author. Department of Thoracic Surgery, First Hospital of Jilin University, No. 71 Xinmin Street, Changchun, China. Tel: ; davidliuw@hotmail.com (W. Liu). Received 23 May 2016; received in revised form 26 July 2016; accepted 19 August 2016 Abstract OBJECTIVES: This systematic review and pooled analysis investigated outcomes and prognostic factors in Non-small-cell lung cancer (NSCLC) patients who underwent surgical treatment for an isolated adrenal metastasis and the primary NSCLC. METHODS: A literature search of PubMed, Embase and Cochrane Library databases was conducted for relevant retrospective studies in patients with NSCLC and isolated adrenal metastatic lesions treated with lobectomy or pneumonectomy and adrenalectomy. Outcome measures were overall, 1-, 2- and 5-year rates stratified by synchronous versus metachronous adrenal metastasis and according to lymph node status, pathology and relative location of the metastasis to the primary tumour. Kaplan Meier curves were generated and differences in were assessed by a log-rank test. RESULTS: Thirteen studies involving 98 patients were included in this analysis. The median overall was 18 months, and the 1-, 2- and 5-year rates were 66.5, 40.5 and 28.2%, respectively. Patients with metachronous adrenal metastasis had a significantly better prognosis than patients with synchronous adrenal metastasis (P < 0.05). Patients classified as negative for lymph node metastasis had a significantly better prognosis than patients classified as positive for lymph node metastasis (P < 0.05). Pathology (squamous carcinoma versus adenocarcinoma) and the relative location of the metastasis to the primary tumour (ipsilateral adrenal metastasis or contralateral adrenal metastasis) had no significant influence on prognosis. CONCLUSIONS: NSCLC patients with isolated adrenal metastasis undergoing surgical treatment for the primary tumour and adrenal metastasis could achieve a significant benefit, especially if they have metachronous adrenal metastasis or are negative for lymph node metastasis. Keywords: Non-small-cell lung cancer Adrenal metastasis Surgical procedures INTRODUCTION Of all cancers, lung cancer is the leading cause of morbidity and mortality worldwide among men, and the fourth leading cause of morbidity and the second leading cause of mortality among women [1]. Non-small-cell lung cancer (NSCLC) is the most common lung cancer, accounting for 85% of all lung cancer cases [2]. At diagnosis, 50% of NSCLC patients have distant metastases [3]. Adrenal gland metastases are frequently noted with NSCLC, and rates of adrenal gland metastasis at autopsy range from 17 to 57% in NSCLC [4, 5]. Of the distant metastases in NSCLC, adrenal glands rank fourth in morbidity following brain, bone and liver [6]. Metastatic involvement limited to the adrenal gland alone in NSCLC patients is rare. The incidence rate is estimated at 1 6% [7]. Because adrenal metastasis is usually accompanied by metastasis to other organs, treatment for adrenal metastasis and NSCLC usually involves nonsurgical therapy including chemotherapy or radiotherapy and the median overall is about 11 months [8]. Management of isolated adrenal metastases in NSCLC is controversial, and includes surgical or conservative treatment options. In 2013, the National Comprehensive Cancer Network guidelines recommended chemotherapy or localized treatments such as local radiotherapy or surgical treatment in cases of isolated adrenal metastasis. With advances in imaging technology [including abdominal computed tomography (CT), ultrasound, magnetic resonance imaging (MRI) and positron emission tomography-ct], laparoscopic surgery and CT/ultrasound-guided fine-needle aspiration [9 11], the detection of isolated adrenal metastasis in NSCLC has increased, and effective management strategies are needed. Several studies have reported that a subset of NSCLC patients with isolated adrenal metastasis achieves a long time through surgical resection of the primary lung cancer and adrenal metastasis [12, 13]. The objective of this pooled analysis was to investigate outcomes and prognostic factors in NSCLC patients who underwent surgical treatment for the primary NSCLC and isolated adrenal metastasis. The Author Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

2 2 MATERIALS AND METHODS X.-L. Gao et al. / Interactive CardioVascular and Thoracic Surgery Statistical analysis Search strategy Two researchers (XL Gao, MB Tang) independently searched the PubMed, Cochrane Library and Embase databases from January 1990 to July 2016 by combining ( lung cancer OR lung carcinoma OR lung neoplasm ) AND ( adrenal metastasis OR adrenal metastases ). The language of articles was restricted to English. Inclusion criteria (i) Retrospective or prospective studies; (ii) patients with NSCLC and isolated adrenal metastatic lesions; (iii) patients treated with segmentectomy, lobectomy or pneumonectomy for primary lung cancer and adrenalectomy for adrenal metastasis. Exclusion criteria (i) Survival data not provided; (ii) studies with less than 3 cases; (iii) nonisolated adrenal metastasis. Study selection Two reviewers (XL Gao, KJ Zhang) independently evaluated titles and abstracts to choose potential studies. If data were duplicated or overlapping, only the most recent data were included. The full text of suitable studies was retrieved. Two reviewers (W Liu, KW Zhang) independently read the full text to determine which articles should be included. Disagreements about article selection were resolved by consensus and discussion. Data extraction and management Two reviewers (XL Gao, MB Tang) independently extracted data from eligible studies including population, pathology, interval and relative position between primary lung cancer and adrenal metastasis, lymph node status and overall time. The outcome measure was overall time, defined as the time from adrenal surgery to death or the last follow-up. Outcome measures were median overall, 1-, 2- and 5-year rates stratified by synchronous versus metachronous adrenal metastasis and according to lymph node status, pathology and relative location of the metastasis to the primary tumour. Adrenal metastasis was classified as synchronous and metachronous based on the time of diagnosis relative to NSCLC. Synchronous adrenal metastasis was defined as presentation of an adrenal metastasis before or within 6 months of NSCLC diagnosis. Metachronous adrenal metastasis was defined as presentation of an adrenal metastasis 6 months after NSCLC diagnosis. N1 and N2 lymph node status (nodal positive versus nodal negative), pathology (squamous carcinoma versus adenocarcinoma) and the relative location of the metastasis to the primary tumour (ipsilateral adrenal metastasis or contralateral adrenal metastasis) were also recorded. Kaplan Meier curves were generated and differences in were assessed by log-rank testing using the SPSS19 software. P < 0.05 was considered statistically significant. RESULTS Study identification The searches identified 172 articles from PubMed, 258 articles from Embase and 10 articles from Cochrane Library. After removing duplicates, 297 studies remained. Abstracts and titles were screened, and 88 articles were considered potentially eligible for surgical management. Full texts of these studies were retrieved. After analysing the full text, 50 studies were excluded because data were inadequately described. Sixteen studies were excluded because the number of patients was less than 3. Nine studies were excluded because they were review articles. Finally, 13 studies were found eligible for inclusion according to our criteria for considering studies in this review [7, 14 25] (Fig. 1). The characteristics of the included studies are given in Table 1. The extent of pulmonary resection was reported in 52 patients from 9 studies in which one segmentectomy, 41 lobectomies or double lobectomies and 10 pneumonectomies were included. The size of adrenal metastasis was described in 66 patients from 9 studies, in which the median was 4.7 cm and the range was cm. Seventy-three patients from 9 studies contained the information about T stage of primary lung cancer (T1 for 7 patients, T2 for 46 patients, T3 for 16 patients and T4 for 4 patients). In 9 studies, 34 patients underwent laparoscopic adrenalectomy, while 15 patients underwent open adrenalectomy. There were only 23 patients with adrenal metastases who were detected at the same time when their primary lung cancers were diagnosed. Ten patients (43.5%) from 4 studies underwent synchronous operations for both primary lung cancer and adrenal metastasis. Ten patients (43.5%) from 2 studies underwent adrenalectomy following lung resection. For other 3 patients (13.0%), the interval between operations for the primary tumour and isolated adrenal metastasis was not described. Patients demographic and clinical characteristics, and univariate analysis of prognostic factors are presented in Table 2. Outcomes Among the 13 included studies, 98 NSCLC patients who underwent surgical treatment for the primary NSCLC and an isolated adrenal metastasis were included in the analysis. The pooled analysis demonstrated a median overall of 18 months (95% CI 11.7, 24.3 months), a 1-year rate of 66.5%, a 2-year rate of 40.5% and a 5-year rate of 28.2% (Fig. 2). Among the 98 NSCLC patients who underwent surgical treatment for the primary NSCLC and an isolated adrenal metastasis, 48 patients had metachronous adrenal metastasis (49.0%) and 50 patients had synchronous adrenal metastasis (51.0%). Patients with metachronous adrenal metastasis had a significantly better prognosis than patients with synchronous adrenal metastasis (median overall, 34 vs 12 months; 1-year rate, 82.5 vs

3 X.-L. Gao et al. / Interactive CardioVascular and Thoracic Surgery 3 THORACIC Figure 1: Flow chart of article selection. Table 1: Characteristics of the included studies No. Author Year of publication Recruitment period Country Patients eligible 1 Kawai [14] Japan 7 2 Chiaki [15] Japan 4 3 Bastian [16] Switzerland 4 4 Muth [17] Sweden 5 5 Shoji [18] Japan 3 6 Sebag [19] France 9 7 Mercier [20] France 23 8 Pfannschmidt [21] Germany 11 9 Lucchi [22] Italy 9 10 Porte [23] France Bendinelli [24] Italy 4 12 Higashiyama [7] Japan 5 13 Reyes [25] USA %; 2-year rate, 53.7 vs 26.7%; 5-year rate 33.1 vs 23.4%) (P = < 0.05, Fig. 3). Eight studies (n = 71 patients) described the influence of lymph node metastasis on the prognosis of patients who underwent surgical treatment for the primary NSCLC and an isolated adrenal metastasis. Thirty-three patients (46.5%) were with accompanying mediastinal or hilar lymph node metastasis (classified as the lymph node positive group) and 38 patients (53.5%) were not (classified as the lymph node negative group). The lymph node negative group had a significantly better prognosis than the lymph node positive group (median overall, 40 vs 13 months; 1-year rate, 71.6 vs 57.9%; 2-year rate, 59.9 vs 27.4%; 5-year rate 48.8 vs 6.3%) (P = < 0.05, Fig. 4). Eleven studies (n = 72) described the influence of pathology on the prognosis of patients who underwent surgical treatment for the primary NSCLC and an isolated adrenal metastasis. Nineteen patients (26.4%) were squamous carcinoma and 53 patients (73.6%) were adenocarcinoma cases. Patients with adenocarcinoma had a better prognosis than patients with squamous carcinoma (median overall, 20 vs 13 months; 1-year

4 4 X.-L. Gao et al. / Interactive CardioVascular and Thoracic Surgery Table 2: Patients demographic and clinical characteristics, and univariate analysis of prognostic factors Patient characteristics Survival analysis Included study Classification Median age (years) Gender (M/F) Median Overall (months) 1-year rate (%) 2-year rate (%) 5-year rate (%) P-value Study No. Eligible number (known the age and gender) Synchronous adrenal metastasis 57.5 (35 78) 36/ (89) Metachronous adrenal 60.0 (44 78) 37/ metastasis Lymph node positive 55.8 (45 76) 32/ , 2, (71) Lymph node negative 61.0 (44 78) 29/ Squamous carcinoma 55.8 (54 68) 17/ , 2, 4, (72) Adenocarcinoma 58.7 (35 78) 43/ Ipsilateral adrenal metastasis 59.6 (54 75) 22/ , 4, 7, 9, (37) Contralateral adrenal metastasis 54.0 (35 77) 15/ Total 58.8 (35 78) 73/ (89) Figure 2: Kaplan Meier estimates of overall for patients undergoing surgical treatment for both primary lung cancer and adrenal metastasis. rate, 70.9 vs 54.3%; 2-year rate, 47.0 vs 34.0%; 5-year rate, 31.7 vs 18.1%), but there was no statistical significance (P = > 0.05, Fig. 5). Seven studies (n = 44) described the influence of metastasis location on the prognosis of patients who underwent surgical treatment for the primary NSCLC and an isolated adrenal metastasis. Nineteen patients (43.2%) were with contralateral adrenal metastasis and 25 patients (56.8%) were with ipsilateral adrenal metastasis. There was no statistical difference in prognosis in patients with contralateral adrenal metastasis (median overall, 17 months; 1-year rate, 61.1%; 2-year rate, 40.7%; 5-year rate, 24.4%) compared with those with ipsilateral adrenal metastasis (median overall, 13 months; 1-year rate, 54.9%; 2-year rate, 30.5%; 5-year rate, 30.5%) (P = > 0.05, Fig. 6). Figure 3: Kaplan Meier estimates of overall : synchronous adrenal metastasis versus metachronous adrenal metastasis. DISCUSSION This pooled analysis of 13 retrospective studies indicates that the median overall of patients with NSCLC and isolated adrenal metastasis treated with segmentectomy, lobectomy or pneumonectomy, and adrenalectomy is 18 months, and that their 1-, 2- and 5-year rates are 66.5, 40.5 and 28.2%, respectively. Improved prognosis in these patients is associated with metachronous adrenal metastasis and no clinical signs of mediastinal or hilar lymph node metastasis. Pathology (squamous carcinoma versus adenocarcinoma), and the relative location of the metastasis to the primary tumour (ipsilateral adrenal metastasis or contralateral adrenal metastasis) had no significant influence on prognosis in this patient population.

5 X.-L. Gao et al. / Interactive CardioVascular and Thoracic Surgery 5 THORACIC Figure 4: Kaplan Meier estimates of overall : lymph node negative versus lymph node positive. Figure 5: Kaplan Meier estimates of overall : squamous carcinoma versus adenocarcinoma. Evidence suggests that the median overall of Stage IV NSCLC patients with adrenal metastasis treated with chemotherapy and local radiotherapy is months [26]. NSCLC patients with Stage IV disease are often diagnosed with multiple disseminated metastases, and patients with isolated foci of metastatic disease are rare. Therefore, treatment of adrenal metastasis in NSCLC has traditionally been nonsurgical. In 1982, Twomey et al. reported a case of large cell lung carcinoma with an isolated adrenal metastasis in which the patient survived 14 years after pulmonary lobectomy and adrenalectomy [27]. In 1996, Luketich and Figure 6: Kaplan Meier estimates of overall : ipsilateral adrenal metastasis versus contralateral adrenal metastasis. Burt retrospectively reviewed NSCLC patients with isolated adrenal metastasis, and reported a median overall of 31 months in 8 patients managed with chemotherapy and adrenalectomy versus 8.5 months in 6 patients managed with chemotherapy alone [28]. In 2005, Mercier et al. demonstrated a 5-year rate of 23.3% in a case series of NSCLC patients who underwent complete resection of an isolated adrenal metastasis after surgical treatment of NSCLC [20]. Similarly, in 2011, Raz et al. showed that the 5-year rate of 20 patients with isolated adrenal metastasis in NSCLC after pulmonary surgery and adrenalectomy was 34%, while the 5-year rate of 17 nonsurgical patients was 0% [29]. Although management of isolated adrenal metastasis from NSCLC is still controversial, these data suggest that surgical treatment may improve long-term. Previous reports have investigated prognostic factors associated with isolated adrenal metastasis in NSCLC. In accordance with the findings in the current study, Tanvetyanon et al. reported that metachronous metastasis in NSCLC patients with isolated adrenal metastasis who underwent adrenalectomy was associated with a longer median overall than synchronous metastasis [12]. The definite reasons for this difference are unclear, but the possible reasons may be that metachronous lesions grow slower or are less aggressive than synchronous lesions. In contrast to this current study, Raz et al. found that the 5-year rate of patients who underwent adrenalectomy for isolated adrenal metastasis and NSCLC that was ipsilateral to their primary tumours had better prognosis than patients with contralateral metastases [29]. With regard to this point, we may need more studies to determine whether metastasis location is the prognostic factor. Besides that, in our study, it was demonstrated that lymph node metastasis was a prognostic factor and pathological type was not. But these viewpoints have not been analysed statistically in other articles until now. Identification of prognostic factors in NSCLC patients with isolated adrenal metastasis may guide treatment decisions that could provide a benefit in well-selected patient populations.

6 6 X.-L. Gao et al. / Interactive CardioVascular and Thoracic Surgery Therapeutic options for patients with NSCLC and isolated adrenal metastasis are evolving. These include stereotactic body radiotherapy and radiofrequency ablation. Notably, tyrosine kinase inhibitors have become first-line treatment for Stage IV NSCLC with epidermal growth factor gene mutations. Further large-scale studies are warranted to compare patient outcomes from these treatment options with surgical management strategies. Although stereotactic body radiotherapy approach has provided a noninvasive treatment option for isolated adrenal metastasis from lung cancer, and the overall response rate was 67%, with 1- and 2-year overall rates 52 and 13%, respectively [30], there still has not been prognostic comparison with surgical treatment. Limitations This study does have some limitations. First, it was limited to retrospective studies. Second, heterogeneity between studies may have been a source of bias. Third, only three studies described adjuvant chemotherapy or radiotherapy, so we could not analyse the influence of chemotherapy or radiotherapy to rates. Last, we could not avoid misdiagnosis of other organ metastases because PET/CT was not applied to all patients, even those patients in the latest articles included in our study. To minimize the bias, randomized controlled trials are required to clearly identify optimal management strategies for NSCLC patients with isolated adrenal metastasis. CONCLUSION In conclusion, the prognosis of NSCLC patients with isolated adrenal metastasis is different from those with other distant metastases. For such patients, surgical treatment for the primary tumour and adrenal metastasis could provide a significant benefit, especially for patients with metachronous adrenal metastasis or those who are classified as negative for lymph node metastasis. Conflict of interest: none declared. 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