24 Ann Thorac Surg 46:24-28, July Copyright by The Society of Thoracic Surgeons

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1 Surgical Management of Lung Cancer with Solitary Cerebral Metastasis John R. Hankins, M.D., John E. Miller, M.D., Michael Salcman, M.D., Frank Ferraro, M.D., David C. Green, M.D., Safuh Attar, M.D., and Joseph S. hklaughlin, M.D. ABSTRACT Betweten 1964 and 1986, 19 patients underwent resection of both a primary lung cancer and the associated brain metastasis. One patient underwent resection of 2 separate primary lung cancers and the associated metastases. The 12 men and 7 women ranged in age from 42 to 67 years (mean, 54.6 years). The cell type was adenocarcinoma in 12 tumors, equamous or adenosquamous cell in 5, large cell undifferentiated or anaplastic in 2, and malignant carcinoid in 1 tumor. The types of resection were as follows: lobectomy for 12 neoplasms, pneumonectomy for 5, bilobectomy for 2, and wedge resection for 1 neoplasm. Radiotherapy to the brain was given in connection with sixteen of the twenty craniotomies. The patient with 2 separate primary neoplasms survived 19 years before dying 5 months after the second craniotomy. The mean survival is 8.0? 2.1 years (& the standard error), and the median survival is 1.67 years. Survival at 1 year was 65 f 10.7% and at 5 years, %. On univariate analysis, the following factors were found to correlate significantly with longer survival: a lung tumor in Stage or 11; negative mediastinal nodes; curative rather than palliative resection of the lung tumor; and age younger than 55 years. However, on multivariate analysis, only curative resection was a significant factor ( p < 0.01). We believe these results justify continued application of this combined surgical approach to patients having limitedstage lung cancer with a solitary brain metastasis. n the United States in 1987, an estimated 150,000 new cases of lung cancer will be diagnosed. Lung cancer is now the most common cause of cancer-related death among both men and women [l]. Considering all cancers, lung cancer is the most common source of brain metastasis [2]. n autopsy series of patients with lung cancer, the incidence of brain metastasis ranges between 30 and 50% [2-41. Some reported series [2, 31 indicated that in up to 30% of patients with lung cancer with brain metastasis, the metastasis is solitary. With nonsurgical methods of treatment, survival of patients with cerebral From the Divisions of 'Thoracic and Cardiovascular Surgery and of Neurological Surgery, Dsepartment of Surgery, University of Maryland School of Medicine, Baltimore, MD Presented at the Thirty-fourth Annual Meeting of the Southern Thoracic Surgical Association, Bota Raton, FL, Nov 5-7, Address reprint requests to Dr. Hankins, University of Maryland Medical System, 22 S Greene St, Baltimore, MD metastasis from lung cancer is poor. The survival of approximately 3 months for untreated patients is lengthened to only 4 to 5 months [5] or at best to 9 months [6] with brain irradiation. Chemotherapy may provide temporary remission with palliation but, to date, has not produced long-term survival [5, 71. Surgical excision of brain metastasis from lung cancer was reported more than 55 years ago by Grant [8] and by Fried and Buckley [4]. However, only in the last 10 to 15 years have reports appeared citing sizable series of patients in whom both the primary lung tumor and the brain metastasis were excised with low operative mortality [2, 9-12]. This report summarizes the experience we have gained since 1964 with excision of the primary lung tumor and its associated metastasis, and includes an anlysis of those clinical variables that may portend long survival. Material and Methods Between May, 1964, and October, 1986,19 patients who had primary lung cancer with a solitary brain metastasis were treated by thoracotomy with resection of the lung cancer and craniotomy with excision of the metastasis. Thirteen of the patients underwent both pulmonary resection and craniotomy in the University of Maryland Medical System/Hospital. n the remaining 6 patients, the pulmonary resection was performed by one of us (J. E. M.) and the craniotomy, by staff neurosurgeons in three private hospitals. The patients included 12 men and 7 women. They ranged from 42 to 67 years old (mean, 54.6 years). There was complete follow-up of these patients: all surviving patients were contacted in August or September, 1987, and all deceased patients were followed until the time of death. One patient had 2 separate primary lung cancers of different cell types occurring in opposite lungs 19 years apart, each of which gave rise to a solitary brain metastasis. Each was treated by craniotomy and excision of the metastatic lesion followed by resection of the primary lung tumor. Therefore, for purposes of statistical analysis, the 2 cancers in this patient are treated as if they occurred in separate patients. The treatment of the initial tumor in this patient was reported previously [13]. Actuarial survival curves were prepared according to the Kaplan-Meier method [14]. The long-rank test of Mantel [15] was used to compare survival curves. Multivariate (multiple regression) analysis was carried out in accordance with the Cox proportional hazards regression model [16]. 24 Ann Thorac Surg 46:24-28, July Copyright by The Society of Thoracic Surgeons

2 25 Hankins et al: Lung Cancer with Cerebral Metastasis Results The initial or presenting symptom was neurological in 13 patients (14 neoplasms, including both tumors in the 1 patient with 2 separate primary tumors). n 12 of these patients (13 tumors), the onset of the metastasis was synchronous with that of the primary in that an asymptomatic lung mass was identified on the chest roentgenogram at the time the patient was admitted for treatment of the metastasis. n such patients, our policy was to carry out the craniotomy first. n the remaining patient, a lung mass was detected on chest roentgenogram 4 months after the craniotomy. The presenting complaint in 5 patients was a pulmonary neoplasm. The interval between the diagnosis of the primary lung tumor and the onset of the cerebral metastasis in these 5 patients ranged from 2 to 11 months (mean, 6.2 months). n the 1 remaining patient, the presenting symptom was neither pulmonary nor neurological but rather arthralgia due to hypertrophic pulmonary osteoarthropathy. Diagnostic studies performed to evaluate this complaint showed both a pulmonary neoplasm and a cerebral mass. n 14 patients (15 neoplasms), the initial operation was a craniotomy. n the remaining 5 patients who were seen with a pulmonary malignancy, it was a pulmonary resection. The tumor cell type was adenocarcinoma in 12 neoplasms, squamous cell or adenosquamous cell carcinoma in 5, large cell undifferentiated or anaplastic carcinoma in 2, and malignant carcinoid in 1. The type of pulmonary resection performed was lobectomy in the case of 12 neoplasms, pneumonectomy in 5, bilobectomy in 2, and wedge resection in 1 neoplasm. (The patient with 2 neoplasms underwent a lobectomy for the first tumor and a wedge resection for the second.) A complete dissection of the mediastinal lymph nodes was carried out in conjunction with nine of the pulmonary resections and a partial dissection with seven others. n the four remaining resections, the mediastinal nodes were inspected but not dissected because they appeared normal grossly. Fifteen resections were considered curative in that no gross tumor was left behind, all resection margins were microscopically tumor free, and the mediastinal nodes were uninvolved. The remaining five resections were considered palliative either because gross tumor was left behind or because the resection margins were inadequate grossly or positive microscopically. n 4 of these 5 patients, the nodal status was N2. n the other patient, there was tumor extension into the chest wall, and the resection had inadequate margins. Postsurgical resection-pathological staging of the primary lung tumors according to the New nternational Staging System [17] revealed that 4 of the tumors were classifiable as T3 tumors, 8 as T2, and 8 as T1. No lymph nodes metastasis (NO) was found in connection with 14 neoplasms, but 2 had metastasized to hilar or peribronchial nodes (Nl), and 4 had mediastinal node metastasis (N2). No patient had known systemic metastases at the time of thoracotomy. However, at the time of fifteen of the pulmonary resections, brain metastases were already known to be present, and therefore, in determining the stage, only the status of the primary tumor and the lymph nodes was considered. By these criteria, 11 of the neoplasms were found to be in Stage, 2 were in Stage 11, and 7 were in Stage A. There was 1 late hospital death. The patient was a 67- year-old woman who underwent resection of a cerebellar metastasis, followed by whole-brain irradiation, followed by a right middle and lower lobectomy with mediastinal node dissection for a Stage A (T2 N2) adenocarcinoma of the lower lobe. Postoperatively, a bronchopleural fistula and empyema developed, which were treated by adequate chest tube drainage and antibiotics with, initially, a satisfactory response. However, the patient remained quite lethargic and anorectic, and it was suspected, though never proven, that the brain metastasis had recurred. Four weeks after lobectomy, cardiopulmonary arrest developed suddenly. The patient was resuscitated but went into ventilator-dependent respiratory failure and ultimately into multisystem failure with sepsis. Death ensued 47 days after lobectomy. Nonfatal complications included a cerebrovascular accident in 1 patient whose ensuing hemiparesis gradually resolved, a myocardial infarction in another patient, and atelectasis requiring bronchoscopy in 2 others. Radiation therapy to the thorax was given to 6 patients postoperatively and to 1 patient preoperatively and through afterloading catheters. Two patients received chemotherapy after they showed evidence of systemic as well as brain metastases. Neither had a measurable response. n the 15 instances among 14 patients in which the craniotomy preceded the thoracotomy, the interval between the two operations ranged from 1.4 to 56 weeks (mean, 9.3? 16.6 weeks [+ the standard deviation {SD}]). Among the 5 patients in whom the thoracotomy preceded the craniotomy, the interval between the two procedures ranged from 24.4 to 52.4 weeks (mean, weeks [+ SD]). The interval between the onset of neurological symptoms and craniotomy ranged from 1 week to 26 weeks (mean, 7.2 weeks). The initial neurological complaint was hemiparesis in 5 patients (6 neoplasms); headache in 6 patients; monoparesis in 2; ataxia in 2; visual disturbances in 2; seizures in 1 patient; and mild weakness of the arm that could be elicited only on careful questioning in 1. The diagnosis of brain metastasis was made by nuclear isotope brain scanning or arteriography or both early in the series. t was made by computed tomographic (CT) scanning in all patients treated since At the time of the craniotomy, the brain lesion was considered on the basis of the preoperative studies to be solitary in the case of 19 of the 20 tumors. n the remaining instance, the patient had been seen with 2 metastatic lesions, 1 large and 1 small. After whole-brain irradia-

3 26 The Annals of Thoracic Surgery Vol 46 No 1 July 1988 tion, the smaller neoplasm was no longer discernible on CT scan. Therefore, only the larger tumor was removed. The site of the metastatic tumor within the brain was found to be frontal in six craniotomies, parietal in two, temporal in two, occipital in one, frontoparietal in two, parieto-occipital in two, frontotemporal in one, and cerebellar in four. n each of the twenty craniotomies, the neurosurgeon indicated that he believed he had accomplished gross total removal of the tumor. There were no hospital deaths. Hemiplegia occurred in 2 patients after craniotomy: it was persistent in 1, and there was gradual partial resolution in the other. Radiation therapy to the brain was given after the second craniotomy in the patient who had 2 separate tumors and after the first craniotomy in 14 other patients. n 7 patients treated mostly early in the series, the dose was 3,000 rads of whole-brain irradiation. n the other 8 patients, a small-field boost of 900 to 2,500 rads to the tumor-bearing area was added after completion of the whole-brain irradiation. The 1 patient with 2 metastatic tumors received 3,000 rads and also chemotherapy before the craniotomy. Amoqg the twenty craniotomies in the 19 patients, relief of the patient s severe neurological symptoms for at least 3 months was afforded by the operation in 17 instances (85%). At 6 months, there was freedom from symptoms in 11 instances (55%); at 1 year, 10 instances (50%); at 2 years, 9 instances (45%); and at 5 years, 4 instances (20%). When the patients who received brain irradiation were compared with those who did not, there was no significant difference in the proportion af patients who were relieved of neurological symptoms or in the duration of the symptom-free period. Two patients underwent a second craniotomy because of suspected recurrent metastasis. n 1, a craniotomy performed 8 months after the original craniotomy and the accompanying whole-brain irradiation disclosed a minute focus of carcinoma at the site of the original metastasis. This was excised, but the patient died of apparent cerebral recurrence and systemic metastases 10 months later. n the other patient, a craniotomy with biopsy 4 years after resection of a cerebellar metastasis (accompanied by 5,500 rads of brain irradiation) revealed only changes consistent with radiation fibrosis. The patient is alive 3% years later, but has incapacitating ataxia. Still another patient required an emergency cervical laminectomy at another hospital 7 months after excision of a cerebellar metastasis, because of a drop metastasis to the cervical spinal canal. The metastasis could not be completely removed. The patient underwent irradiation to the tumor bed, but died 5% months later of persistent cancer compressing the spinal cord. At the time of this report, 7 patients are alive and without evidence of recurrent cancer. Twelve have died, including the patient who died 47 days after lobectomy. Death was caused by recurrent cancer in 10 patients. t was in the form of widespread systemic metastases in 5, recurrent central nervous system metastases in 2, and a combination of central nervous system and systemic Ourroll Survivol a 30 2l A 20 Yeors Fig 1. Survival after twenty craniotomies in 19 patients. Survival at 1 year was 65 f 10.7% (2 the standard error) and at 5 years, 45 f 11.1%. Mean survival was 8.0 f 2.1 years and median survival, 1.67 years Brain Radiation (16 pta., 6 censored 1 median = 1.67 yrs - No Radiat/on ( 4 pts.. censoted ) > median yra. 50 lo Yeors Fig. 2. Survival afler craniotomy was not significantly differeat for the 16 instances when brain irradiation was given compared with the 4 when it was not. metastases in 3. One patient died of pneumonia and respiratory failure complicating severe chronic obstructive pulmonary disease 17 months after the craniotomy. Survival after the craniotomy ranged from 2.8 months to 19.2 years. Mean survival was 8.0 f 2.1 years (5 the standard error [SE]) and the median survival, 1.67years. Survival was 65 f 10.7% (f SE) at 1 year, 45 * 11.1% at 2 years, 45 * 11.1% at 5 years, and 38 * 11.5% at 10 years (Fig 1). There was no significant difference in survival between those who received brain irradiation in connection with the craniotomy and those who did not (Fig 2). The following variables were analyzed to determine their effect, if any, on survival: age; sex; order of presentation (cerebral symptoms first, pulmonary symptoms first, or synchronous presentation); interval between thoracotomy and craniotomy if the thoracotomy was done first; interval between operations if the craniotomy

4 27 Hankins et a1 Lung Cancer with Cerebral Metastasis 04:, Cwotive Resecfion [ 15 pts., 7 censored 1 median = 12.1 yrs RVllofive Resection ( 5 pts., 0 censored 1 median yr,,,,,,, /) Years Fig 3. Survival after craniotomy in 15 instances of curative resection of the lung tumor compared with that in 5 instances of palliative resection. Curative resection afforded significantly longer survival (p < on univariate analysis; significance was confirmed on multivariate analysis). - Tumor-fm medm8tim/ no&@ ( NoorNl~116ptr.,7cm~ored~ median 5.0 yn 1 / Years Fig 4. Survival after craniotomy in 16 instances of tumor-free mediastinal nodes compared with 4 instances of positive mediastinal nodes. Tumor-free nodal status was associated with significantly longer survival (p < on univariate analysis; this was not confirmed on multivariate analysis). was done first; neoplasm cell type; type of pulmonary resection (pneumonectomy, bilobectomy, lobectomy, wedge resection); curative or palliative pulmonary resection; T classification of the lung tumor (T1 or T2 versus T3); nodal status (NO or N1 versus N2); lung tumor stage (Stage, 11, or A); duration of neurological symptoms prior to craniotomy; location of the brain metastasis (frontal lobe versus other sites); and brain radiotherapy versus no radiotherapy. By univariate analysis, four factors were found to correlate with significantly longer survival: curative pulmonary resection ( p < 0.001) (Fig 3); nodal status NO or N1 ( p < 0.001) (Fig 4); lung tumor Stage or (p < 0.01); and age less than 55 years ( p < 0.05). However, when all four of these variables were included in a Cox multivariate model, only curative resection remained a significant prognostic factor for longer survival ( p < 0.01). Comment Surgical excision of single brain metastasis from lung cancer results in longer survival than nonsurgical methods of treatment [6, 121. Patchell and colleagues [6] noted a median survival of 19 months in a group of 43 patients with solitary brain metastasis from non-small cell lung cancer treated by surgical excision plus brain irradiation compared with a median survival of only 9 months in a matched group of 43 patients treated by brain irradiation alone. The fact that patients with brain metastasis may have no neurological symptoms, as was true of 1 of our 19 patients, has led us to recommend the routine preoperative performance of a cranial CT scan in patients with operable lung carcinomas. When an asymptomatic solitary brain metastasis is detected on a routine CT scan of the brain in a patient with a resectable lung lesion, ordinarily the craniotomy is carried out first and the pulmonary resection soon afterward. However, if there is a suspicion that either the lung neoplasm or the brain metastasis is unresectable, we agree with Martini [18] that the surgical approach should be directed initially to the site where there is the greater question about resectability. For example, in a patient whose brain metastasis is small and superficial but whose lung neoplasm is central with questionable involvement of the mediastinum, the initial procedure should be one that definitively determines the resectability of the lung tumor. n general, if either the lung or the brain lesion is unresectable, the patient should be treated by nonsurgical methods. There are, however, certain exceptions to this rule. f the size or location (for example, in the posterior fossa) of the brain metastasis is such that it constitutes an immediate limiting factor to the length or quality of the patient's survival, resection of the metastasis should be attempted regardless of the resectability of the lung tumor [19]. The mean survival, median survival, and 1-year survival of 8.0? 2.1 years, 1.67 years, and 65? 10.7% in our series compare favorably with the corresponding figures of 2.3? 3.8 years, 1.1 years, and 55? 7.9% in the series of combined resections reported by Magilligan and co-workers [12]. n the series of Sundaresan and Galicich [ll], the 1-year survival was 50% and in that of Deviri and colleagues [2], 64%. The 1-year survival in the series of Ehrenhaft [20] involving 40 patients treated by surgical removal of both sites of cancer was 35%. Magilligan and associates [ 121 analyzed sixteen clinical variables and found that only wedge resection, as opposed to more extensive resections, significantly influenced survival. From this, they inferred that the size of the lung neoplasm might directly affect survival. n contrast, we found that neither tumor size and location (T classification) nor extent of the pulmonary resection was a significant predictor of survival.

5 28 The Annals of Thoraac Surgery Vol 46 No 1 July 1988 Our findings are more in agreement with those of Sundaresan and Galicich [ll], who found that curative resection of the lung tumor, negative mediastinal nodes, and metastatic disease limited to the central nervous system were favorable prognostic indicators. n our series, curative resection of the lung tumor was a significant indicator of longer survival on both univariate and multivariate analysis, and NO or N1 nodal status correlated significantly with survival on univariate analysis. n none of our patients was there known extracranial metastasis at the time of the combined resection. Therefore, in terms of this variable, our series cannot be compared with that of Sundaresan and Galicich [ll]. n our series, lung tumor stage was a significant factor on univariate analysis, although it was not significant on multivariate analysis. These findings suggest that more thorough preoperative staging of the primary tumor might eliminate some patients who will not benefit from combined resection. Our series differs from other reported series of combined resection of both the lung neoplasm and the brain metastasis [2, 9-12] in that in 14 of 20 instances, the patient s initial symptom was neurological. This is in contrast with the series of Magilligan and associates [12] in which only 14 of 41 patients had neurological symptoms when initially seen, and with that of Sundaresan and Galicich [ll] in which only 14 of 50 patients were seen with such symptoms when first seen. n our series, the predominance of patients with neurological symptoms when initially seen is probably related to our having a very active neurooncology service with a large referral base. n 13 of the instances of neurological presentation in our series and in 1 additional instance in which the patient had neither pulmonary nor neurological symptoms, the lung and brain lesions were detected simultaneously or synchronously. Sundaresan and associates [lo, 111 consider synchronous onset of metastasis to be a generally adverse prognostic factor. However, in their 1985 report [ll], they could not demonstrate a significant difference in survival between their patients with synchronous onset of metastasis and those with metachronous onset. Likewise, we failed to find a significant difference in survival between patients with the two types of onset. Both survival and neurological palliation of patients with lung cancer and solitary cerebral metastasis could be improved if there were a more effective method of controlling the brain neoplasm [ll, 121. This is evidenced by the fact that recurrent central nervous system metastasis was either the principal or a contributory cause of 5 of our 10 deaths from cancer. ncreasing the dose of external irradiation to the brain carries with it the risk of radiation fibrosis or necrosis of the brain. The answer may lie instead with interstitial irradiation through afterloading catheters, a technique our neurosurgeons have recently begun to implement. On the other hand, when recurrent brain metastases do develop and are solitary, as is often the case, a repeat resection should be attempted. n the series of Magilligan and associates [12], a second craniotomy resulted in a 1-year survival of 30%. We thank John R. Hebel, Ph.D., Professor of Epidemiology and Preventive Medicine, and Charles M. Suter, Ph.D., Assistant Professor of Surgery, University of Maryland School of Medicine, for statistical analysis of the survival data. References 1. Silverberg E, Lubera JA Cancer statistics, Ca 385, Deviri E, Schachner A, Halevy A, et a1 Carcinoma of lung with a solitary cerebral metastasis. Cancer , Galluzzi S, Payne PM. Brain metastases from primary bronchial carcinoma: a statistical study of 741 necropsies. Br J Cancer 10408, Fried BM, Buckley RC: Primary carcinoma of the lungs: V. ntracranial metastases. 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Cancer nvest 3:107, Magdigan DJ Jr, Duvemoy C, Malik G, et al: Surgical approach to lung cancer with solitary cerebral metastasis: twenty-five years experience. Ann Thorac Surg 42360, Mosberg WH Jr: Twelve-year cure of lung cancer with metastasis to the brain. JAMA , Kaplan EL, Meier P: Non-parametric estimation from incomplete observations. J Am Stat Assoc 53:457, Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50363, Cox DR Regression models and life-tables. J R Stat SOC 34:187, Mountain CF: A new international staging system for lung cancer. Chest 89 suppl:225s, Martini N: Rationale for surgical treatment of brain metastasis in non-small cell lung cancer (editorial). Ann Thorac Surg 42:357, Salcman M Metastatic brain tumors: diagnostic and therapeutic management. Contemp Neurosurg 1(26):1, Ehrenhaft JL: Discussion of Magdigan et a1 [12]