Key words: brain neoplasms; lung neoplasms; neoplasm metastasis; neurosurgery; survival rate; thoracic surgery

Surgical Management of Non-small Cell Lung Cancer With Synchronous Brain Metastases* Pierre Bonnette, MD; Philippe Puyo, MD; Christophe Gabriel, MD; Roger Giudicelli, MD; Jean-François Regnard, MD; Marc Riquet, MD; Pierre-Yves Brichon, MD; and the Groupe Thorax Objectives: Published series on the synchronous combined resection of brain metastases and primary non-small cell lung cancer are small and scarce. We therefore undertook a multicenter retrospective study to determine long-term survival and identify potential prognostic factors. Design: Our series includes 103 patients who were operated on between 1985 and 1998 for the following tumors: adenocarcinomas (74); squamous cell carcinomas (20); and large cell carcinomas (9). Three patients had two brain metastases, and one patient had three metastases; the remaining patients had a single metastasis. Ninety-three patients presented with neurologic signs that regressed completely after resection in 60 patients and partially, in 26 patients. Neurosurgical resection was incomplete in six patients. Seventy-five patients received postoperative brain radiotherapy. The time interval between the brain operation and the lung resection was < 4 months. Pulmonary resection was incomplete in eight patients. Results: The survival calculated from the date of the first operation was 56% at 1 year, 28% at 2 years, and 11% at 5 years. Univariate analysis showed a better prognosis for adenocarcinomas (p 0.019) and a trend toward a better prognosis for patients with small pulmonary tumors (T1 vs T3, p 0.068), N0 stage disease (N0 vs N, p 0.069), and complete pulmonary resection (p 0.057). In a multivariate analysis, adenocarcinoma histology also affected the survival rate (p 0.03). Conclusions: It seems legitimate to proceed with lung resection after complete resection of a single brain metastasis, at least in patients with an adenocarcinoma and a small lung tumor and without abnormal mediastinal lymph nodes seen on the CT scan or during mediastinoscopy. (CHEST 2001; 119:1469 1475) Key words: brain neoplasms; lung neoplasms; neoplasm metastasis; neurosurgery; survival rate; thoracic surgery Abbreviations: NSCLC non-small cell lung cancer; WBRT whole-brain radiotherapy Bronchogenic carcinoma is the cancer that most commonly metastasizes to the brain and accounts for 50% of brain metastases. 1 Unfortunately, once metastatic brain disease develops, the cancer has already widely disseminated. 2 Seven percent of *From the Department of Thoracic Surgery (Drs. Bonnette and Puyo) and the Department of Statistics (Dr. Gabriel), Hôpital Foch, Suresnes, France; the Department of Thoracic Surgery (Dr. Giudicelli), Hôpital Ste-Marguerite, Marseille, France; the Department of Thoracic Surgery (Dr. Regnard), Hôpital Marie Lannelongue, Le Plessis-Robinson, France; the Department of Thoracic Surgery (Dr. Riquet), Hôpital Laënnec, Paris, France; and the Department of Thoracic Surgery (Dr. Brichon), Hôpital La Tronche, Grenoble, France. A complete list of Groupe Thorax investigators and participating centers is located in the Appendix. Manuscript received June 27, 2000; revision accepted November 15, 2000. Correspondence to: Pierre Bonnette, MD, Service de Chirurgie Thoracique, Hôpital Foch, BP 36, 40 rue Worth, 92151 Suresnes, France; e-mail: pierre.bonnette@wanadoo.fr patients present with neurologic symptoms pointing to the presence of a solitary brain metastasis from bronchial cancer. 3 Patients with brain metastases from non-small cell lung cancer (NSCLC) have a poor prognoses. Treatment modalities include corticosteroids, chemotherapy, external-beam radiotherapy, stereotactic radiosurgery, or neurosurgery. Combined neurosurgical resection and radiotherapy usually leads to rapid and lasting regression of symptoms and may prolong survival by decreasing neurologic morbidity and mortality. 4,5 According to Patchell et al, 4 25% of patients with a single brain metastasis from various primary tumor sites would benefit from curative neurosurgery. If the decision to resect a single brain metastasis revealing a NSCLC may be readily taken, resection of the primary lung tumor is more controversial. 6 CHEST / 119 / 5/ MAY, 2001 1469

Many articles 7 11 reporting the results of series with patients who have undergone dual resection have been published, and some have reported extended survival 12 ( 10 years). Such series, however, are small and date back some years. In light of these facts, we undertook a multicenter retrospective study to determine the long-term survival time, to identify potential prognostic factors, and to define the indications for adjuvant treatment after synchronous resection of brain metastasis and primary lung cancer. Patient Characteristics Materials and Methods A questionnaire was sent to the members of the Groupe Thorax, a group of French thoracic surgeons, to collect data on all patients who had undergone surgery between January 1985 and December 1998. At that time, standard investigations included at least a CT scan of the chest, a CT scan or MRI scan of the brain, and a CT scan or ultrasound of the abdomen. Isotope bone scans were not routinely performed. The operations were to have been performed 4 months apart. Tumor histology had to be that of a squamous carcinoma, an adenocarcinoma, or a large cell lung cancer. Thirteen surgical centers (see Appendix ) responded and provided data for 103 patients. Four teams had operated on 16 patients. Patients included 89 men and 14 women. The mean age was 54 years, with a range of 32 to 85 years. Histology showed 74 adenocarcinomas (including one bronchioloalveolar carcinoma), 20 squamous cell carcinomas, and 9 large cell lung cancers. Ninety-four patients had undergone neurosurgery first (nine of these patients had no neurologic signs, and their brain metastases had been discovered in the course of lung cancer localization studies). Nine patients had undergone thoracic surgery first. The time between the two operations was 30 days for 36 patients, between 31 and 60 days for 36 patients, between 61 and 90 days for 22 patients, and between 91 and 120 days for 9 patients. Among the last nine patients, seven presented with neurologic signs warranting neurosurgery before thoracic surgery, and two developed neurologic signs during the immediate postoperative period after lung surgery. The mean time between the two operations was 46.2 days (46 days when neurosurgery was performed first and 47.7 days when lung surgery was performed first). Forty-one patients received the following perioperative chemotherapy: 6 patients received one or two courses of chemotherapy before any surgery; another 6 patients received one to four courses of chemotherapy between the two operations; and 31 patients received chemotherapy after the second operation (1 patient received four courses between the two operations and four courses after the second operation, and 1 patient received two courses before the first operation and four courses after the second operation). Neurosurgical Aspects Ninety-three patients had neurologic signs before neurosurgical resection, as follows: motor deficit (35 patients); intracranial hypertension (18 patients); convulsions (17 patients); headaches (14 patients); cerebellar syndrome (10 patients); and miscellaneous other signs (9 patients). Some patients had more than one neurologic sign. A single metastasis was found in 99 patients, two metastases were found in 3 patients, and three metastases were found in 1 patient. Complete neurosurgical resection was achieved in 97 patients, and resection was incomplete in 6 patients (2 of whom were among the 4 patients with several metastases). The site of the metastases was supratentorial in 84 patients, infratentorial in 16 patients, both supratentorial and infratentorial in 2 patients (among the 4 patients with several metastases), and unspecified in 1 patient. Postoperative recovery was generally uncomplicated, no patient died and one patient developed postoperative adrenal failure. After surgery, a complete regression of signs was achieved in 60 patients and incomplete regression was achieved in 26 patients; neurologic signs persisted in 6 patients and worsened in 1 patient. Seventy-five patients received brain radiotherapy, and 26 did not; information on radiotherapy was missing for two patients. When a radiotherapy dose was provided, it ranged from 20 to 50 Gy; however, the specific technique was not described and may have been simple radiotherapy to the resection site, whole-brain radiotherapy (WBRT), or WBRT with a booster dose to the resection site. Thoracic Aspects Sixty-nine patients underwent lobectomies, 25 underwent pneumonectomies, 2 had segmentectomies, and 7 had wedgeresection. Chest wall resection was required in four patients. Resection remained incomplete in eight patients. Two patients died, one after pulmonary artery suture rupture 10 days after undergoing a lobectomy, and the other of a pulmonary embolism 36 days after undergoing a pneumonectomy. Morbidity was observed in five patients and included one postpneumonectomy fistula, one postpneumonectomy empyema, one serious pulmonary infection after pneumonectomy, one pulmonary abscess after lobectomy, and one case of acute ischemia of a limb. Lung tumor staging is given in Table 1. Thirty-three patients, including 3 patients with stage N0 and 30 patients with stage N disease, received radiotherapy to the thorax. When the radiotherapy dose was indicated, it ranged between 45 and 55 Gy. Methods This was a multicenter retrospective study. Participating surgeons were asked to provide data on tumor recurrence sites and on the cause of death. However, the primary survival data often were obtained from the vital statistics department. Survival time was calculated from the date of the first operation. Survival curves were calculated using the nonparametric Kaplan-Meier method. 13 Univariate comparison of survival was carried out by log-rank analysis, 14 and multivariate analysis was performed using the Cox proportional hazards model. 15 Table 1 Staging of the Primary Pulmonary Tumor* Stage *? status unknown. Patients, No. T1 23 T2 61 T3 16 T4 2 T? 1 N0 40 N1 23 N2 35 N3 1 N? 4 1470 Clinical Investigations

Results No patient died after undergoing a craniotomy. Two deaths occurred 10 and 36 days after thoracotomies. Seven patients were lost to follow-up but were not known to have recurrences, and 15 patients, including 1 with a brain recurrence, were still alive at the time of the study (October 1999). The mean length of follow-up was 17.3 months. Two patients died of intercurrent causes. Forty-five patients had brain recurrences, which was single in 22 patients and was associated with other localizations in the remaining 23 patients (7 thoracic sites and 18 other sites). Nineteen of these 45 patients (42%) had not received brain radiotherapy. In many cases, it was impossible to determine whether the recurrence was at the same site as the first metastasis or elsewhere in the brain. Only 14 patients developed a thoracic recurrence (ipsilateral, contralateral, mediastinal, pleural, etc), which was a single recurrence in 2 patients, was associated with a brain recurrence in 7 patients, and was associated with distant metastases in 5 patients. Nineteen patients had tumor dissemination with no brain and/or thoracic recurrence. The four patients who were operated on with two or three brain metastases died after 12, 13, 15, and 32 months. The calculated survival rate (Kaplan-Meier method) for the 103 patients was 56% at 1 year, 28% at 2 years, 13% at 3 years, and 11% at 5 years (Fig 1). The median length of survival was 12.4 months. Univariate analysis was used to identify potential predictive factors. Histology was found to affect survival. Patients with adenocarcinomas had a better prognosis than those with squamous cell carcinomas (p 0.019) [Fig 2]. Survival curves drawn on the Figure 2. Survival time of patients with primary adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Patients with adenocarcinomas had a significantly prolonged survival time (p 0.019). basis of the T staging of the pulmonary tumor seemed to show a decrease in survival time from stage T1 to stages T2 and T3, but the difference was not significant, even between stages T1 and T3 (p 0.068) (Fig 3). Similarly, the survival curve for stage N0 tumors (n 40) seemed better than for that for stage N tumors (n 59), but the difference was not significant (p 0.069) (Fig 4). The difference between complete lung resection (n 95) and incomplete lung resection (n 8) was not significant (p 0.057) [Fig 5]. Furthermore, there was no significant difference between complete and incomplete neurosurgical resection, between brain radiotherapy and no radiotherapy, between radiotherapy to the chest or no radiotherapy, between men and women, between Figure 1. Overall survival time from the time of the first procedure in 103 patients undergoing resections of brain metastases and primary lung cancer. Figure 3. Survival time according to the T status of the primary lung cancer. Survival tended to be shorter in patients with later T stages, but the difference did not achieve significance. CHEST / 119 / 5/ MAY, 2001 1471

Figure 4. Survival time according to the N status of the primary lung cancer. Survival time tended to be shorter in patients with later N stage, but the difference did not achieve significance. supratentorial or infratentorial resection, and between chemotherapy or no chemotherapy (p 0.13). Multivariate analysis of these data using the Cox proportional hazards model to clarify the independent roles of histology, locoregional staging, chemotherapy, and complete pulmonary resection showed that complete resection (p 0.52), the T (p 0.14) and N (p 0.12) staging, and chemotherapy (p 0.07) did not significantly affect survival time but that adenocarcinoma histology did (p 0.03). Discussion The diagnosis of synchronous lung cancer and a single metastasis usually rules out surgical resection as a therapeutic option. Small series 16,17 of the resection of both lung cancer and adrenal metastases have been published. Several larger series with brain metastases have been published. 7 11 Our study provides one of the largest series reported in the literature. Because the first patients were operated on in 1985, all patients were investigated with a CT scan of the thorax and a CT scan or an ultrasound of the abdomen. Brain investigations used a CT scan or MRI scan, but we do not know how many patients had MRI scans. Schellinger et al 18 reported that among the 55 patients showing a solitary brain metastasis on the CT scan, 17 (31%) showed multiple metastases on the MRI scan. It is therefore essential to obtain an MRI scan before proceeding with the resection of a brain metastasis. Most of our patients had neurologic signs. External beam radiotherapy may alleviate symptoms and prolong the median survival time. However, neurosurgery remains an important therapeutic option in selected patients with a single superficial metastasis. Two randomized trials by Patchell et al 4 and Vecht et al 5 concluded that the addition of surgery before radiotherapy increased survival time and improved neurologic function and quality of life compared with radiotherapy alone in patients with a single metastatic brain tumor (Table 2). Yet, in a multicenter randomized trial, Mintz et al 19 failed to detect a difference in survival or quality of life between patients who underwent surgery plus radiotherapy and those who received radiotherapy alone. The patients included in that trial, however, had a low baseline median Karnofsky performance score, and many had extracranial metastases. These differences may explain why no survival benefit was derived from surgical removal. Brain recurrences remain common after neurosurgical resection of a brain metastasis (44% in our series). They may be either local (at the site of the original tumor) or distant (elsewhere in the brain). In a randomized trial, Patchell et al 20 observed that the rate of tumor recurrence in the brain was significantly lower when patients received postoperative WBRT (18% vs 70%; p 0.001). This benefit was apparent for both local (10% vs 46%; p 0.001) and distant recurrences (14% vs 37%; p 0.01), but no statistically significant difference was observed in the median survival time (48 vs 43 weeks; p 0.39). In our series, the postoperative brain radiotherapy provided to 75% of the patients did not affect survival time; however, 42% of the patients with a brain recurrence received no radiotherapy. Nevertheless, WBRT can be associated with significant short-term and delayed toxicity. Figure 5. Survival time in patients who had locoregional primary disease, whether or not resection was complete. The survival time tended to be shorter in patients who had undergone incomplete resections (p 0.057). 1472 Clinical Investigations

Table 2 Survival Time for Patients With a Single Brain Metastasis from Various Primary Cancers in Trials of Radiation Alone vs Surgery Plus Radiation* Study/Year Subjects, No. Radiation Alone, mo Surgery and Radiation, mo p Value Patchell et al 4 /1990 48 3.45 9.28 0.01 Vecht et al 5 /1993 63 6.00 10.00 0.04 Mintz et al 19 /1996 84 6.28 5.62 0.24 *Values given as median, unless otherwise indicated. Stereotactic radiosurgery also is used to treat a single brain metastasis. The hospital stay is short, and the response on symptoms is slower than with neurosurgery. WBRT is often given at the same time. This treatment modality is reserved for tumors measuring 3 cm and is recommended for deep lesions. In the absence of any randomized study comparing radiosurgery and surgery, opinions diverge on the quality of local tumor control and the place of radiosurgery when neurosurgical resection is feasible. 21,22 In several retrospective studies, 9,23 univariate analysis has shown improved survival times when both the primary lung tumor and brain metastases are resected, whether lung surgery is performed long before neurosurgery (metachronous presentation) or at the same time (synchronous presentation). In a series of 113 patients reported by Harpole et al, 23 brain lesions were treated by either neurosurgical resection (n 52) or stereotactic radiosurgery (n 61) and WBRT. The median survival time was 11 months. A significant benefit was observed for patients who underwent complete lung tumor resection (n 86; median survival time, 16 months; p 0.001), had negative lymph nodes (n 50; median survival time, 18 months; p 0.01), or had stage I or II lung lesions (n 56; median survival time, 18 months; p 0.004). the number of metastases, the histology, the timing of surgery (metachronous, 60 patients; synchronous, 53 patients), or the treatment modality of the brain lesions did not affect survival time. The nodal stage was the only significant factor in a multivariate analysis. Synchronous brain and lung resection series are generally very small (Table 3). Torre et al 7 published a report on a series of 27 patients, of whom 21 underwent synchronous surgery. The overall 5-year survival rate was 15%, and the mean survival time was 26 months. Better results were obtained in patients without node metastases at the time they underwent thoracotomy and in patients with supratentorial metastases. Rossi et al 8 reported on a series of 40 patients who had bifocal resection. The 1-year survival rate was 35%, the 2-year survival rate was 25%, and the 5-year survival rate was 12.5%. All patients surviving for 2 years had a Karnofsky index score of 50 and stage N0 disease after staging. In a series of 185 consecutive patients undergoing resection of brain metastases, Burt et al 9 analyzed 65 patients with synchronous brain metastases (diagnosed 60 days after the primary NSCLC). The 32 patients who underwent complete lung resections had survival rates of 71%, 16%, and 16% at 1, 5, and 10 years, respectively (median survival time, 21 months), compared with survival rates of 40%, 4%, and 0% at 1, 5, and 10 years, respectively, for patients who did not have complete resections (median survival time, 10 months). Multivariate analysis demonstrated that locoregional stage had no significant effect on survival time (p 0.97) but that complete resection of the primary disease significantly prolonged survival time (p 0.002). Mussi et al 10 reported on a series of 45 patients who underwent bifocal resections. The 5-year survival rate for the 15 patients with synchronous presentation was 6.6% with a median survival of 18 months; 14 of these patients died within 30 months. Table 3 Results of Combined Surgery in Some Series Survival Rate, % Study Years of Study Subjects, No. 1 year 2 years 5 years Torre et al 7 1975 1987 27 15 Rossi et al 8 Not specified 40 35 25 12.5 Burt et al 9 1974 1989 32 71 16 Mussi et al 10 1975 1992 15 6.6 Present series 1985 1998 103 56 28 11 CHEST / 119 / 5/ MAY, 2001 1473

Only one patient survived for 5 years (survival time, 63 months). The only variable that was significantly associated with a longer survival time was a squamous lung cancer histology (p 0.02). Our series was a multicenter, retrospective series, so that patient management may have varied from one center to another. The large sample allows for the multifactorial analysis of parameters that may have affected survival. All patients underwent modern radiologic investigations. The difference in survival time between patients with stages N0 and N tumors appears to be less obvious in our series (the difference was not significant) than in the other series 7,8,10 in which authors often advise performing a mediastinoscopy and reserving lung resection for patients with stage N0 tumors. In France, for the last 15 years, many patients with a clinical N2 staging on CT scans were operated on without mediastinoscopy, and we do not know in our series how many patients had clinical N0 or N2 staging and how many patients were operated on after negative results of a mediastinoscopy. The better prognosis for patients with adenocarcinomas that was observed in our series also was found by Burt et al 9 but without a significant difference. Age often is considered to be a prognostic factor, 8 but this was not the case in our series. Last, chemotherapy failed to show any benefit. However, patient management has evolved since the first patients in our series were treated (1985). New drugs have been developed, 24 and more is known about drug penetration into the brain, which allows us to hope for more effective chemotherapy, whether it is neoadjuvant, intercurrent (between the two operations), or adjuvant after combined surgery. Conclusion In the absence of any randomized, comparative study, combined surgery on brain metastases and the primary lung tumor seems to prolong survival time. In our series, factors such as the size of the lung tumor and lymph node status affected prognosis to a certain extent. Adenocarcinoma is a favorable prognostic factor in our study, as opposed to other published series. It seems legitimate to proceed with lung resection after complete resection of a single brain metastasis, at least in patients with a small lung tumor and no abnormal mediastinal lymph nodes seen on the CT scan or during mediastinoscopy. Brain radiotherapy is usually advisable to reduce the risk of local recurrences. The value and timing of chemotherapy remain to be defined (neoadjuvant, intercurrent, or adjuvant after the resection of both sites). Appendix The following Groupe Thorax investigators and centers in France participated in the study: F. Bellenot, MD (Argenteuil); P. Bonnette, MD (Suresnes); P.Y. Brichon, MD (Grenoble); M. Dahan, MD (Toulouse); A. Dujon, MD (Rouen); J.M. Faillon, MD (Lille); R. Giudicelli, MD (Marseille); G. Grosdidier, MD (Nancy); A. Joyeux, MD (Nîmes); M. Monteau, MD (Reims); J.F. Regnard, MD (Le Plessis-Robinson); M. Riquet, MD (Laënnec); and D. Van Raemdonck, MD (Leuven). References 1 Walker AE, Robins M, Weinfield FD. Epidemiology of brain tumors: the national survey of intracranial neoplasms. Neurology 1985; 35:219 226 2 Arbit E, Wronski M. Clinical decision making in brain metastases. Neurosurg Clin North Am 1996; 7:447 459 3 Albain KS. Survival determinants in extensive stage non-small cell lung cancer: the Southwestern Oncology Group. J Clin Oncol 1991; 9:1618 1626 4 Patchell RA, Tibbs PA, Walsh JW, et al. A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 1990; 322:494 500 5 Vecht CJ, Haaxma-Reiche H, Noordijk E, et al. Treatment of single brain metastasis: radiotherapy alone or combined with neurosurgery. 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18 Schellinger PD, Meinck HM, Thron A. Diagnostic accuracy of MRI compared to CCT in patients with brain metastases. J Neurooncol 1999; 44:275 281 19 Mintz AH, Kestle J, Rathbone MP, et al. A randomized trial to assess the efficacy of surgery in addition to radiotherapy in patients with a single cerebral metastasis. Cancer 1996; 78:1470 1476 20 Patchell RA, Tibbs PA, Regine WF, et al. Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial. JAMA 1998; 280:1485 1489 21 Sawaya R. Intracranial metastatic tumor management: surgical treatment of brain metastases. Clin Neurosurg 1999; 45:41 47 22 Alexander E, Loeffler JS. Intracranial metastatic tumor management: the case for radiosurgery. Clin Neurosurg 1999; 45:32 40 23 Harpole D, Amos A, Alexander E, et al. Stage of the primary is important when treating isolated brain metastases from lung cancer. Proc Am Soc Clin Oncol Annu Meet 1996; 15:A1143 24 Bunn PA, Kelly K. New combinations in the treatment of lung cancer. Chest 2000; 117:138S 143S 3 rd ACCP SCCM Combined Critical Care Course August 1 0-14 Orlando World Center Marriott CHEST / 119 / 5/ MAY, 2001 1475