Nonsurgical treatment of solitary adrenal metastases

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1 Resection of Adrenal Metastases From Non-Small Cell Lung Cancer: A Multicenter Study Henri Porte, MD, PhD, Joëlle Siat, MD, Benoit Guibert, MD, Francoise Lepimpec-Barthes, MD, René Jancovici, MD, Alain Bernard, MD, Annick Foucart, MD, and Alain Wurtz, MD Clinique Chirurgicale, Hôpital A. Calmette Centre Hospitalier et Universitaire de Lille, Lille, France Background. In recent case reports and limited series, adrenalectomy was recommended for an isolated adrenal metastasis from non-small cell lung cancer (NSCLC). Methods. We retrospectively studied patients with a solitary adrenal metastasis from NSCLC who had undergone potentially curative resection in eight centers. Results. Forty-three patients were included. Their adrenal gland metastasis was discovered synchronously with NSCLC in 32 patients, and metachronously in 11. It was homolateral to the NSCLC in 31 patients and contralateral in 12 (p < 0.01). Median survival was 11 months, and 3 patients survived more than 5 years. There was no difference between the synchronous and metachronous groups regarding recurrence rate or survival. Survival was not affected by the homolateral location of the metastasis, the histology of the NSCLC, TNM stage, any adjuvant and neoadjuvant treatment, or, in the metachronous group, a disease-free interval exceeding 6 months. Conclusions. We confirm the possibility of long-term survival after resection of isolated adrenal metastasis from NSCLC, but no clinical or pathologic criteria were detected to identify patients amenable to potential cure. (Ann Thorac Surg 2001;71:981 5) 2001 by The Society of Thoracic Surgeons Nonsurgical treatment of solitary adrenal metastases (AM) from non-small cell lung cancer (NSCLC) is associated with poor survival. The impact of adrenal resection cannot be clearly evaluated from the literature, which mainly consists of case reports concerning longterm survivors after lung and adrenal resection [1 4]. Furthermore, the few published series include less than 20 patients with resected AM from NSCLC [5 11], because of the relative rarity of truly isolated AM. Accordingly, in two prospective studies [5, 11] these AM were evaluated, respectively, at 1.62% and 3.5% of resectable NSCLC. In the present study, we report the results of a retrospective multicenter study of patients with AM from NSCLC, both of which were surgically treated with a potentially curative aim during the past 10 years, and analyze the clinical and pathologic factors that may have affected survival. Patients and Methods From 1987 to 1998, all patients who had been surgically treated for NSCLC associated with a solitary resectable AM in eight thoracic surgery centers were included in the study. Data were obtained from medical records, physicians interviews, or clinical examinations. Patients in whom any other metastatic deposit had been detected before operation were excluded, as were patients who Accepted for publication Oct 18, Address reprint requests to Dr Porte, Clinique Chirurgicale, Hôpital Calmette, Bd du Professeur Leclercq, Lille Cedex, France; awurtz@ chru-lille.fr. had a macroscopically incomplete resection of the primary tumor or AM. Patients with involvement of mediastinal lymph nodes were included in the study. These patients had not systematically received preoperative chemotherapy but they all received postoperative mediastinal radiotherapy. After adrenalectomy, no particular criteria were defined to give any adjuvant treatment including radiotherapy focalized on the adrenal bed, or platinum-based chemotherapy protocols. Unilateral AM, identified at the time of initial NSCLC diagnosis, were classified as synchronous. Metastases shown to be absent at the time of lung resection were classified as metachronous. Before operation, all patients underwent thoracic, cerebral, and abdominal computed tomographic scan. A positron emission tomographic scan was never performed. Complete resection was defined as the absence of any microscopical tumor after lung and adrenal resection. In patients with synchronous metastasis, the disease-free interval was defined as zero. In patients with metachronous metastasis, it was defined as the time from the resection of the primary NSCLC to adrenalectomy. In both groups, follow-up was calculated from the date of adrenalectomy. Patient survival was expressed by actuarial analysis according to the Kaplan- Meier method, using time zero as the date of adrenalectomy and death as the end point. In both groups, diseasefree survival was defined as the interval from the date of adrenalectomy to the date of the last follow-up or diagnosis of disease recurrence. Data are expressed as frequency distributions and simple percentages. Univariate analysis of the selected variables was done by 2 analysis by The Society of Thoracic Surgeons /01/$20.00 Published by Elsevier Science Inc PII S (00)

2 982 PORTE ET AL Ann Thorac Surg ADRENALECTOMY FOR LUNG CANCER METASTASIS 2001;71:981 5 Table 1. Surgical Treatment and Pathological Characteristics of Primary Non-Small Cell Lung Cancer (NSCLC) in 43 Patents Who Underwent Adrenalectomy for Adrenal Gland Metastases (AM) Primary NSCLC Characteristics Synchronous AM (n 22) Metachronous AM (n 21) Total (n 43) Adenocarcinoma Squamous cell Large cell Adenosquamous T1N T2N T2N T2N T3N T3N T3N T4N Lobectomy and bilobectomy Enlarged lobectomy or bilobectomy Pneumonectomy Enlarged pneumonectomy Multivariate analysis was done with the same variables by Cox regression model. Statistically significant differences were defined as p equal to 0.05 or less. The primary NSCLC variables tested for potential significant association with AM were histology, TN status, and location on the operated lung (superior lobe, inferior lobe). Variables tested for potential influence on survival were primary NSCLC histology, TNM status, synchronous or metachronous group, disease-free interval in the metachronous group, surgical approach to perform adrenalectomy, and any adjuvant or neoadjuvant treatment. Results Primary NSCLC Characteristics and Treatment Forty-three patients were included in the study (11 had been included in a previous report [11]); 22 had synchronous AM and 21, metachronous AM. They comprised 38 men and 5 women whose mean age was 52 years (range, 34 to 75 years). Table 1 shows the surgical treatment and pathologic characteristics of primary NSCLC in the 43 patients. Except for adenocarcinomatous nature (p 0.01), none of the pathologic parameters of primary NSCLC was found to be significantly associated with the occurrence of an adrenal metastasis. Resection of the primary NSCLC was complete in 41 patients (95%); there was microscopical bronchial stump involvement in 1 patient, and microscopical chest wall margin involvement in 1 patient. Before lung resection, a mean of two cycles (range, 1 to 3 cycles) of platinum-based chemotherapy (mean dose, 80 mg/m 2 ) was given to 3 patients (7%) who had histologically proved N2 involvement. All the patients (n 16) with N2 involvement ascertained after systematic mediastinal lymphadenectomy, received postoperative radiotherapy (mean, 60 Grays) focalized on the mediastinum. AM Characteristics and Treatment The AM was diagnosed by computed tomographic scan in all 43 patients. It was confirmed by computed tomographic-guided biopsy in 18 patients, and by operation in the remaining 25 patients. The AM was homolateral to the primary NSCLC in 31 patients (72%, p 0.01), 16 of whom were synchronous and 15, metachronous. It was contralateral in 12 patients (6 synchronous and 6 metachronous). The mean size of the AM was 5.6 cm (range, 2 to 12.5 cm). Adrenalectomy was performed through lumbotomy in 18 patients, laparotomy in 14, and phrenotomy during thoracotomy in 11. Twelve of the 22 patients with synchronous AM were resected at the time of lung resection, 6 after lung resection (mean, 5 weeks) and 4 before lung resection (mean, 7 weeks). Adrenalectomy was complete in all patients. In 2 patients, associated nephrectomy was necessary because of kidney involvement by the AM. Regional lymph node dissection was not routinely performed. Mortality during operation and the 30 days thereafter was nil. During those 30 days, postoperative morbidity affected 8 patients and was always the result of lung operation. Six patients received postoperative radiotherapy (mean, 60 Grays) focalized on the adrenal bed. Twelve of them received platinumbased chemotherapy after adrenalectomy (mean dose, 100 mg/m 2 ; mean, 4 cycles; range, 1 to 6 cycles). Follow-up and Recurrence The mean follow-up period was months (range, 2 to 94 months); it was months for synchronous AM, and months for metachronous AM. In the metachronous group, the postoperative disease-free interval was 15.7 months (range, 3 to 40 months). Thirty-four of the 43 patients (80%) developed a recurrence of their lung cancer during follow-up, including 15 with synchronous AM (68%) and 19 with metachronous AM (90%, p 0.05). The cases of recurrence comprised 24 of the 31 patients with homolateral AM (77%) and 10 of the 12 with contralateral AM (83%, p 0.05). In 19 of the 34 patients who had a lung cancer recurrence (56%), it developed during the 6 months after adrenalectomy, and in 13 (38%), during the first 3 months. The sites of recurrence in the 34 patients are given in Table 2; the disease-free survival period and the recurrence rate for the 43 patients are given in Table 3. In the 7 patients whose recurrence was located in the adrenal gland bed, the AM was resected through lumbotomy in 4 patients, laparotomy in 2, and phrenotomy in 1 patient. Survival Twenty-eight patients died of their lung cancer (65%), and 4 (9%) of other causes. Five (11.6%) were alive with recurrent lung cancer, and 6 (14%) were alive and free of recurrent disease, respectively 3, 16, 17, 76, 92, and 94

3 Ann Thorac Surg PORTE ET AL 2001;71:981 5 ADRENALECTOMY FOR LUNG CANCER METASTASIS 983 Table 2. Site and Number of Lung Cancer Recurrence in 34 of 43 Patients Who Underwent Adrenalectomy for Adrenal Gland Metastases Site of Recurrence Synchronous Metachronous months after adrenalectomy. The 2-, 3-, and 4-year actuarial survival were 29%, 14%, and 11%, respectively. Survivals rate of the 43 patients are given in Table 3. The Kaplan-Meier survival curve for the 43 patients is given in Figure 1. There was no significant difference between survival in the synchronous, metachronous, homolateral, and contralateral groups. In both groups neither survival nor the disease-free interval (in the metachronous group) was affected by primary NSCLC histology, TNM stage, surgical approach to adrenalectomy, or adjuvant or neoadjuvant treatment. Comment All Patients Brain Bone Liver Contralateral adrenal gland Abdomen Soft tissue Peripheral lymph node Lung Adrenal gland bed Some patients had several sites of recurrence. The value of operation in the cure of patients with metastatic disease has been overlooked during the past two decades, especially for cancers that do not respond well to systemic chemotherapy. As a general principle, patients with a single site of metastatic disease that can be resected without major morbidity should undergo resection of that metastasis if the primary neoplastic site can be (or was) also surgically treated in a curative intent [12]. In this setting, the surgical management of NSCLC that has metastasized to other sites has for the most part been confined to patients with metastasis to other pulmonary segments or to the brain. As for metastatic disease to the liver or bone, the surgical treatment for AM from NSCLS has not been widely adopted, first, because of concern about the probability of associated advanced diffuse metastases, and second, because the incidence of truly solitary AM in patients with operable NSCLC is low. Consequently, it was generally thought that adrenal metastases (even solitary) precluded any further surgical intervention. However, in case reports and a few small series, it was stressed that selected patients with an isolated AM can undergo resection with reasonable long-term survival [1 11]. These observations were reinforced by studies of patients undergoing resection at other distant metastatic sites, such as patients with a solitary brain metastasis who benefited from the resection of both primary NSCLC and the metastatic tumor [13 15]. Thus, Patchell and coworkers [13], who compared surgical resection plus radiotherapy to radiotherapy alone for single brain metastases from many primary sites, mostly the lung, found that the surgical resection group lived longer and had fewer recurrences of NSCLC in the brain than the group given radiotherapy alone. With regard to solitary AM from NSCLC, Luketich and colleagues [9], who reported a recent series of 14 patients, suggested that in certain cases, chemotherapy followed by surgical resection may be better than chemotherapy alone. The present results confirm that the adenocarcinomatous type of NSCLC is more frequently associated with AM, and that a solitary AM is more frequently located on the same side as the primary NSCLC [11, 16]. We also confirm the possibility of long-term survival, although this is certainly rarer than is suggested in some individual case reports. With respect to metachronous metastases, we could not confirm the results of Higashiyama [6] and Kim [10] and their associates, who found that a disease-free interval of less than 6 months was linked to poorer survival, due to the intrinsic biological aggressiveness of the tumor and its metastases. Furthermore, we did not observe any difference between the recurrence rate or survival of the synchronous and metachronous groups. Overall, the present series does not provide many helpful indications, either with regard to the identification of patients who would benefit from operation, or with regard to how much the surgical procedure influenced survival in these patients. The long-term survivors probably constitute a selected group whose tumors were biologically indolent. Nevertheless, our study, with 3 of 43 long-term survivors and a median survival of 11 months, confirms the data reported by Kim and colleagues [10], who obtained a disease-free survival of 11 months in a series of 37 patients, including 17 with NSCLC. This strengthens the Table 3. Disease-Free Survival, Recurrence Rate, Mean and Median Survival Rate for the 43 Patients Affected by Primary Non-Small Cell Lung Cancer Who Underwent Adrenalectomy for Adrenal Gland Metastases (AM) Synchronous AM (n 22) Metachronous AM (n 21) Total (n 43) p Value Mean disease-free survival Recurrence rate 15 (68%) 19 (90%) 34 (80%) 0.05 Mean survival rate 14.7 (SD 2.5) 15.3 (SD 2.4) 16.2 (SD 2.1) NS NS not significant; SD standard deviation.

4 984 PORTE ET AL Ann Thorac Surg ADRENALECTOMY FOR LUNG CANCER METASTASIS 2001;71:981 5 Fig 1. Survival of the 43 patients who underwent surgical treatment of primary nonsmall cell lung cancer and solitary adrenal gland metastasis calculated with the Kaplan-Meier method. (* Effective sample size for the compilate of the actuarial life curve.) conclusion that surgical resection seems the best option for a potential cure, or at least the best palliative therapy compared to nonsurgical treatments. Accordingly, few reports have been published on the role of radiotherapy on adrenal metastases [16 18]. Soffen and colleagues [17] reported the results of palliative radiotherapy in 9 patients with lung carcinoma and an isolated AM, whose median survival was 6 months. Only Miyaji and coworkers [19] reported a case of long-term survival exceeding 34 months after radiotherapy for a metachronous AM, in a patient who underwent resection of the primary NSCLC. Similarly dismal results were recently reported for chemotherapy in two limited series [6, 9], whose median survival periods were less than 6 and 8.5 months, respectively. The longest survival period in these series was 22 months, and there were no long-term survivors. The main problem of concern is to establish preoperatively that the AM is truly isolated. In the present series, 56% of the patients developed their recurrent lung cancer within the 6 months after adrenalectomy, and 38% within the first 3 months, which reflected the presence of multiple nondetectable lesions at the time of operation, despite complete staging. These early recurrences lead us to conclude first, that the staging modalities were not accurate enough, and second, that cases of advanced NSCLC (ie, stage III), which have a high metastatic potential, should not be surgically treated when associated with isolated AM, despite the nonsignificant incidence of TNM stage on survival in our study. Therefore, we now propose that in patients with stage I or II NSCLC and a supposedly solitary AM, preoperative staging should at least include a positron emission tomographic scan, cerebral magnetic resonance imaging, and mediastinoscopy. For patients with synchronous AM, neoadjuvant chemotherapy can be given, as advocated by Luketich and associates [15]. With regard to operation for AM, simple adrenalectomy seems enough. Dissection of regional lymph nodes of the affected adrenal gland should not always be performed because of this procedure s potential morbidity, except when AM is associated with an extraglandular extension which has to be treated by extensive resection of the invaded organs (lymph nodes kidney) through an elective approach. On the contrary, the large number of patients with a recurrence in the adrenal bed regardless of the surgical approach used argues in favor of systematic adjuvant radiotherapy delivered to the adrenal bed. In conclusion, long-term survival may be achieved in some patients after adrenalectomy for AM from NSCLC in a small percentage of patients, but these cases cannot be identified by any of the preoperative results studied here. Nevertheless, we propose the following prerequisites as a guide to patient selection: (1) complete potential control of the primary NSCLC; (2) exclusion of patients with stage III NSCLC; (3) the most up-to-date explorations before operation, to confirm the solitary nature of the AM and minimize the chances of early recurrence; (4) similar management of synchronous and metachronous AM with regard to staging and operative strategy, and (5) the transdiaphragmatic approach as the method of choice for synchronous AM resection when no other structure is invaded by the neoplastic process. References 1. Twomey P, Montgomery C, Clark O. Successful treatment of adrenal metastases from large-cell carcinoma of the lung. JAMA 1982;248: Raviv G, Klein E, Yellin A, Schneebaum S, Ben-Ari G. Surgical treatment of solitary adrenal metastases from lung carcinoma. J Surg Oncol 1990;45: Reyes L, Parvez S, Nemoto T, Regal AM, Takita H. Adrenalectomy for adrenal metastasis from lung carcinoma. J Surg Oncol 1990;44: Kirsch AJ, Oz MC, Stoopler M, Ginsburg M, Steinglass K. Operative management of adrenal metastases from lung carcinoma. Urology 1993;42: Ettinghausen S, Burt ME. Prospective evaluation of unilateral adrenal masses in patients with operable non small cell lung cancer. J Clin Oncol 1991;9: Higashiyama M, Doi O, Kodama K, Yokouchi H, Imaoka S, Koyama H. Surgical treatment of adrenal metastasis following pulmonary resection for lung cancer: comparison of adrenalectomy with palliative therapy. Int Surg 1994;79:

5 Ann Thorac Surg PORTE ET AL 2001;71:981 5 ADRENALECTOMY FOR LUNG CANCER METASTASIS Ayabe H, Tsuji H, Hara S, Tagawa Y, Kawahara K, Tomita M. Surgical management of adrenal metastasis from bronchogenic carcinoma. J Surg Oncol 1995;58: Lo CY, Van Heerden JA, Soreide JA, Grant CS, Thompson GB, Lloyd RV, Harmsen WS. Adrenalectomy for metastatic disease to the adrenal glands. Br J Surg 1996;83: Luketich JD, Burt ME. Does resection of adrenal metastases from NSCLC improve survival? Ann Thorac Surg 1996;62: Kim SH, Brennan MF, Russo P, Burt ME, Coit DG. The role of surgery in the treatment of clinically isolated adrenal metastasis. Cancer 1998;82: Porte H, Roumilhac D, Graziana JP, et al. Adrenalectomy for a solitary adrenal metastasis from lung cancer. Ann Thorac Surg 1998;65: Rosenberg SA. Principles of cancer management: surgical oncology. In: De Vita VT, Hellman S, Rosenberg SA. Cancer: principles and practice of oncology. Philadelphia: Lippincott Raven, 1997: Patchell R, Tibbs P, Walsh J, et al. A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 1990;322: Burt M, Wronski M, Arbit E, Galicich JH. Resection of brain metastasis from non-small-cell lung carcinoma. Results of therapy. Memorial Sloan-Kettering Cancer Center Thoracic Surgical Staff. J Thorac Cardiovasc Surg 1992;103: Luketich JD, Martini N, Ginsberg RJ, Rigberg D, Burt ME. Successful treatment of solitary extracranial metastases from non-small cell lung cancer. Ann Thorac Surg 1995;60: Karolyi P. Do adrenal metastases from lung cancer develop by the lymphogenous or hematogenous route? J Surg Oncol 1990;43: Soffen EM, Solin LJ, Rubenstein JH, Hanks GE. Palliative radiotherapy for symptomatic adrenal metastases. Cancer 1990;65: Short S, Chaturvedi A, Leslie MD. Palliation of symptomatic adrenal gland metastases by radiotherapy. Clin Oncol 1996; 8: Miyaji N, Miki T, Itoh Y, et al. Radiotherapy for adrenal gland metastasis from lung cancer: report of three cases. Radiation Med 1999;17:71 4. New Requirements for Recertification/Maintenance of Certification in 2001 Diplomates of the American Board of Thoracic Surgery who plan to participate in the recertification/ maintenance of certification process in 2001 should pay particular attention to this notice because the requirements have changed. In addition to an active medical license and institutional clinical privileges in thoracic surgery, effective in 2001, a valid certificate is an absolute requirement for entrance into the recertification/maintenance of certification process. If your certificate expired, the only pathway for renewal of a certificate will be to take and pass the Part I (written) and the Part II (oral) certifying examinations. In 2001, the American Board of Thoracic Surgery will no longer publish the names of individuals who have not recertified. In the past, a designation of NR (not recertified) was used in the American Board of Medical Specialties directories if a Diplomate had not recertified. The Diplomate s name will be published upon successful completion of the recertification/maintenance of certification process. The CME requirements have also changed. The new CME requirements are 70 Category I credits in either cardiothoracic surgery or general surgery earned during the 2 years prior to application. SESATS and SESAPS are the only self-instructional materials allowed for credit. Category II credits are not allowed. The Physicians Recognition Award for recertifying in general surgery is not allowed in fulfillment of the CME requirements. Interested individuals should refer to the 2001 Booklet of Information for a complete description of acceptable CME credits. Diplomates should maintain a documented list of their major cases performed during the year prior to application for recertification. This practice review should consist of 1 year s consecutive major operative experiences. If more than 100 cases occur in 1 year, only 100 should be listed. Candidates for recertification/maintenance of certification will be required to complete both the general thoracic and the cardiac portions of the SESATS selfassessment examination. It is not necessary for candidates to purchase SESATS individually because it will be sent to candidates after their application has been approved. Diplomates may recertify the year their certificate expires, or if they wish to do so, they may recertify up to two years before it expires. However, the new certificate will be dated 10 years from the date of expiration of their original certificate or most recent recertification certificate. In other words, recertifying early does not alter the 10-year validation. Recertification/maintenance of certification is also open to Diplomates with an unlimited certificate and will in no way affect the validity of their original certificate. The deadline for submission of applications for the recertification/maintenance of certification process is May 1 each year. A brochure outlining the rules and requirements for recertification/maintenance of certification in thoracic surgery is available upon request from the American Board of Thoracic Surgery, One Rotary Center, Suite 803, Evanston, IL 60201; telephone number: (847) ; fax: (847) ; abts_ evanston@msn.com by The Society of Thoracic Surgeons Ann Thorac Surg 2001;71: /01/$20.00 Published by Elsevier Science Inc