brain metastases: histology, multiplicity, surgery, and survival

1781

Brain Metastases Histology, Multiplicity, Surgery, and Survival

Eric S. Nussbaum, M.D.'

Hamid R. Djalilian, M.D.'

Kwan H. Cho, M.D?

Walter A. Hall, M.D."~

' Department of Neurosurgery, University of Minnesota Hospital and Clinic, Minneapolis, Minnesota.

Department of Radiation Oncology, University of Minnesota Hospital and Clinic, Minneapolis, Minnesota.

Address for reprints: Walter A. Hall, M.D., De- partment of Neurosurgery, Box 96 UMHC, 420 Delaware Street SE, Minneapolis, MN 55455.

Received February 27, 1996; revision received June 13, 1996; accepted June 28, 1996.

0 1996 American Cancer Society

BACKGROUND. With the advent of new therapies for metastatic carcinoma to the brain, patterns of intracranial disease and factors influencing survival become important considerations when examining potential treatment options. METHODS. The records of 729 patients with metastases to the brain treated during the period between 1973 to 1993 were reviewed. RESULTS. Primary tumor histologic type in order of descending frequency included nonsmall cell lung carcinoma (NSCLC), breast carcinoma, small cell lung carcinoma (SCLC), malignant melanoma, renal cell carcinoma, gastrointestinal carcinoma., uterine/vulvar carcinoma, and unknown primary carcinoma. There were 384 patients (53%) with a single brain metastasis, which was encountered most commonly in patients with prostate carcinoma and least often in patients with SCLC. Multiple metastases were present in 345 patients (47%). The median duration from diagnosis to presentation with a brain metastasis was 12 months, ranging from 3 months for patients with NSCLC to 53 months for patients with breast carcinoma. The median duration from presentation with brain metastases to death was 4 months, ranging from 3 months for patients with SCLC to 13 months for patients with prostate carcinoma. Median survival from presentation with brain metastases to death was 5 months for patients with single lesions and 3 months for pati'ents with multifocal disease ( P = 0.0001). Median survival for patients with a single lesion was 11 months with surgery and 3 months without surgery ( P =

0.0001). Surgery did not significantly influence survival in patients with multiple metasta,ses. CONCLU!SIONS. Dissemination of systemic carcinoma to the brain continues to carry a poor prognosis. Knowledge of the metastatic patterns and limited survival associated with specific tumor types may be useful for guiding future therapeutic intervention. Cancer 1996; 78:1781-8. 0 I996 American Cancer Society.

KEYWORCIS brain neoplasm, metastasis, surgery, survival.

n 1994, it was estimated that there were 1,208,000 newly diagnosed I cases of cancer in the US. and 538,000 annual deaths caused by cancer.] Each year in the U.S. more than 100,000 cancer patients develop brain metastases.' The reported incidence of dissemination of systemic cancer to the brain ranges from 20-40%, depending on whether autopsy, surgical, or radiologic data is reviewed."' The abso- lute frequency of metastatic carcinoma to the brain is thought to be increasing as cancer patients live longer because of earlier diagnosis and more effective treatment regimens.5s6 Estimates of prevalence further increase as the ability to detect malignant dissemination im- proves, with brain metastases now recognized as the most common intracranial tumor, even outnumbering primary lesion^.^,^

Despite diagnostic and therapeutic advances, the optimal treatment for ,patients with metastatic carcinoma to the brain remains

1782 CANCER October 15, 1996 / Volume 78 / Number 8

Months I FIGURE 1, Kaplan-Meier survival curves after neurologic presentation based on multiplicity of lesions. The length of time from neurologic presentation to death was significantly shorter (log rank test, P < 0.OOOi) in the 345 patients with multiple metastases (thin line) than in the 384 patients with solitary lesions (bold line) (median length of survival, 3 mos vs. 5 mos; relative risk of death, 1.54; standard error of relative risk, 0.08).

controversial. When considering treatment options, the patterns of intracranial dissemination and factors influencing survival become important prognostic variables. In this study, the disease patterns and survival in 729 patients with metastatic brain tumors were evaluated, with special emphasis on the differences between specific tumor types and the impact of surgical intervention.

MATERIALS AND METHODS Patient Population A retrospective review of medical records identified 729 patients (350 men and 379 women) with documented brain metastases treated at the University of Minnesota Hospital and Clinic (UMHC) from 1973 to 1993. Follow-up from the time of initial diagnosis until the time of death was obtained in 654 cases (90%). Fifty-two patients (7%) were still alive at the time of follow-up and 23 patients (3%) were lost to follow-up. In all cases, the presence of a brain metastasis was confirmed by computed tomography (CT) of the head, magnetic resonance (MR) imaging of the head, or pathologic examination of tissue obtained at the time of tumor biopsy or resection. This report includes all patients encountered during the CT era (the time since UMHC had access to a prototype CT scanner in 1973). Patients with carcinomatous meningitis with or without brain metastases were excluded from the study.

For each patient, the site and histologic type of

primary cancer (if known), treatment of the primary tumor, duration from initial diagnosis to presentation with brain metastases, neurologic signs and symptoms on presentation, location of the brain metastases, multiplicity of brain metastases, treatment of brain metastases, and duration of survival after presentation with brain metastases were recorded. When a single metastasis was present, the exact location was documented. For multifocal disease, the metastases were grouped into the following categories based on their aggregate locations; cerebrum, cerebrum and cerebellum, cerebellum alone, or brainstem. In those patients who were lost to follow-up, the tumor type, treatment of the primary tumor, duration from diagnosis to presentation with brain metastases, clinical presentation, and treatment of brain metastases were still recorded. These patients were excluded from statistical analysis of survival patterns. Of note, UMHC has no regional bias to specific tumor histologies with the exception of hematologic malignancies.

Statistical Analysis Using this data, survival curves were constructed for each primary tumor type. The time from initial diagnosis to presentation with brain metastases and the duration from presentation with neurologic involvement

Brain MetastaseslNussbaum et al. 1783

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FIGURE 3. Kaplan-Meier survival curves for patients with a single brain metastasis according to treatment group. Patients with single brain metastases lived significantly longer (log rank test, P < 0.0001) if they received surgical treatment (thin line; n = 158) for their metastases' than if they did not have surgery (bold line; n = 210) (median surviva'l, 11 months vs. 3 months). The relative risk of death without surgery was 2.12 (standard error of relative risk, 0.12).

to death were examined. In addition, the significance of tumor multiplicity on survival was assessed. The impact of surgical therapy was analyzed for the entire cohort and then separately for patients with either single lesions or multifocal disease. Survival analyses were performed using the Kaplan-Meier product- limit method.8 If patients were alive at last follow-up, they were treated as censored data. Using the log rank test, the difference between survival curves was evaluated.g The effects on survival of presenting signs and symptoms, patient age, tumor location, and treatment with surgery, radiation therapy, or chemotherapy were assessed in univariate and multivariate analyses using the Cox proportional hazards model and the log rank test."

Treatment Philosophy An aggressive approach was taken for patients with metastatic brain tumors treated at UMHC:. Patients with well controlled systemic disease and a single, surgically accessible brain metastasis were treaited by resection of the tumor followed by whole brain radiation therapy (WBRT). The majority of patients who had WBRT received 3000 centigray total in 10 fractions. Patients with advanced systemic disease or with an estimated survival of fewer than 3 months were usually treated with WBRT alone. Patients with well controlled systemic disease and multiple metastases had WBRT

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FIGURE 4. Kaplan-Meier survival curves for patients with multiple metastases according to treatment group. A statistically significant difference in the survival of patients with multiple metastases was not found based on surgical treatment (log rank test, P > 0.05). The group that received surgery (thin line; n = 13) had a median survival of 6 months (95% confidence interval [CI], 3-14 months); and the group that had no surgical treatment (bold line; n = 325) had a median survival of 3 months (95% CI, 2-3 months).

and, at times, adjuvant chemotherapy. In select cases, patients with multiple brain metastases underwent surgical excision of a single tumor that was producing significant neurologic compromise. Occasionally, patients with two adjacent metastases had both lesions resected via the same surgical approach. There was significant selection bias associated with choosing those patients that had surgery for either single or multiple metastases that probably influenced their overall length of survival.

RESULTS Patient Characteristics and Treatment One hundred and seventy-eight patients (24%) had nonsmall cell lung carcinoma, 121 (17%) had breast carcinoma, 110 (15%) had small cell lung carcinoma (SCLC), 80 (11%) had malignant melanoma, 45 (6%) had renal cell carcinoma, 45 (6%) had gastrointestinal carcinoma, 38 (5%) had uterinelvulvar carcinoma, 33 (5%) had metastases from an unknown primary site, 14 (2%) had ovarian carcinoma, 14 (2%) had bladder carcinoma, 11 (2%) had prostate carcinoma, 11 (2%) had testicular carcinoma, and 29 (4%) had rniscellane- ous cancers. Tumors in the miscellaneous category included solid metastases in patients with lymphoma or leukemia, soft tissue sarcomas, and tumors of osse- ous origin.

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TABLE 1 TABLE 3 Presenting Signs or Symptoms in 729 Patients with Brain Metastases Primary Tumor Type in 729 Patients with Brain Metastases

Sign or symptom No. of patients (%) Primary type No. total (%) No. single (%) No. multiple (W)

Headache Altered mental status Seizure Paresis Gait disturbance visual complaints Nausealvomiting Dysphasia Sensory disturbance None

178 (24) 173 (24) 119 (16) 118 (16) 66 (9) 44 (6) 37 (5) 33 (5) 12 (2) 74 (10)

TABLE 2 Distribution of Lesions in 729 Patients with Brain Metastases

Location No. of patients 1%)

Single lesions Frontal Parietal Cerebellum Occipital Temporal Brainstem

Multiple lesions Cerebrum Cerebrum & cerebellum Cerebellum Brainstem

136 (19) 93 (13) 70 (10) 42 (6) 33 (5) 10 (1)

241 (33) 89 (12) 10 (1) 5 (1)

Neurologic signs and symptoms at presentation, in descending order of frequency, were headache, altered mental status, seizure, paresis, gait disturbance, visual complaints, nausealvomiting, dysphasia, and sensory disturbance (Table 1). In 10% of patients there were no symptoms, and the brain metastases were discovered incidentally on a screening radiographic examination. Forty patients (6%) presented with acute symptoms due to intratumoral hemorrhage. The incidence of hemorrhage was highest with malignant melanoma (18%), testicular carcinoma (18%), renal cell carcinoma (9%), and ovarian carcinoma (7%).

There were 384 cases (53%) of a single brain metastasis, located in the following areas: frontal (36%), parietal (24%), temporal (9%), occipital (1 l%), cerebellum (18%), and brainstem (2%) (Table 2). Multiple metastases were present in 345 patients (47%), involving the cerebrum (70%), cerebrum and cerebellum (26%1, cerebellum (3%), or brainstem (1%). Multiple metastases were observed most commonly with SCLC (44%). The cerebellum was involved most commonly by metastases from primary gastrointestinal carcinomas

NSCLC Breast SCLC Melanoma Renal cell Gastrointestinal Uterinelvulvar Unknown Ovarian Bladder Prostate Testicular Miscellaneous Total

89 (50) 59 (49) 48 (43) 39 (49) 25 (56) 30 (67) 20 (53) 23 (70) 8 (57) 9 (64) 9 (82) 6 (55) 19 (65) 384 (53)

89 (50) 62 (51) 62 (56) 41 (51) 20 (44) 15 (33) 18 (47) 10 (30) 6 143) 5 (36) 2 118) 5 (45) 10 (35) 345 (47)

NSCLC: nonsmdl cell lung Carcinoma; SCLC: small cell 1un.e carcinoma.

(31%). Table 3 summarizes the frequency of single or multiple metastases for each histologic tumor type.

All patients were treated with corticosteroids and 624 patients (86%) underwent WBRT. In the remaining cases, patients either refused WBRT or died before the completion of radiation therapy. One hundred and forty patients (19%) received adjuvant chemotherapy for their systemic disease. One hundred and seventy- one patients (23%) had surgery for 1 or more brain metastases. Twenty-one patients (3%) with metastatic lesions were treated with stereotactic radiosurgery. Of those patients who had stereotactic radiosurgery, 11 had 1 brain metastasis and 10 had multiple lesions.

The 345 patients with multiple metastases and the 384 patients with single metastases were well matched for primary tumor histology, sex, and age. Of the patients with single metastases, the 158 who underwent surgery and the 210 who did not were well matched for primary tumor histology, age, sex, tumor location, and treatment with radiation therapy and chemotherapy.

Survival The median duration from diagnosis to presentation with brain metastases was 12 months, ranging from 3 months for SCLC to 53 months for breast carcinoma. Patients with brain metastases from an unknown primary location presented with symptoms due to neurologic disease and were not included in this calculation. The median duration from presentation with brain metastases to death was 4 months, ranging from 3 months for SCLC to 13 months for prostate carcinoma. The data for the individual primary tumor types are summarized in Table 4.

Brain MetastaseslNussbaum et al. 1785

TABLE 4 Survival T i e s for Primary Tumor Types in 729 Patients with Brain Metastases

Diagnosis to Metastasis to Diagnosis to Primary tumor trpe metastasis (mos) death (mos) death (mos)

NSCLC Breast SCLC Melanoma Renal cell Gastrointestinal Uterinelvulvar Unknown Ovarian Bladder Prostate Testicular Miscellaneous Total Cohort

3 40 6 31 28 14 23 <: 1 23 15 22 15 16 12

4 4 3 5 6 3 3 7 8 3 3 4 3 4

10 53 10 41 46 22 27 8 32 23 31 21 30 19

NSCLC nonsmall cell lung carcinoma; SCLC small cell lung carcinoma.

Median survival after presentation with brain metastases was 5 months for patients with single lesions and 3 months for multifocal disease (Figs. 1, 2) (log rank test, P = 0.0001). Median survival for patients with single lesions was 11 months with surgery (158 patients) and 3 months without surgery (210 patients) (Fig. 3) (log rank test, P = 0.0001). Mediam survival times for patients with multiple metastases were 6 months with surgery (13 patients) and 3 months without surgery (325 patients) (Fig. 4) (log rank test, P = 0.0683). The median survival from presentation with brain metastases was 5 months in patients younger than 60 years of age (347 patients), and 3 months in patients 60 years of age or older (359 patients) (log rank test, P = 0.0051). Median survival times with surgery are inclusive of radiation therapy. The effects of tumor multiplicity and surgical intervention on survival are summarized in Table 5.

The median survival for the 11 patients with single brain metastases who were treated with stereotactic radiosurgery was 15.4 months compared with 6.6 months for the 10 patients with multiple lesions re- ceiving this therapy. This difference in survfval was not significant because of the small numbers of patients in each group (log rank test, P = 0.1058). Overall survival for all 21 patients who had radiosurgery was 9.9 months, which is comparable to the 11-month median survival for patients with surgically resecteld single lesions treated with WBRT. The survival rates for patients with single metastases who were treated with surgery or radiosurgery were not compared because of the small size of the latter group.

For all patients, univariate analysis documented a statistically significant improvement in survival with surgery (P = O.OOOl), radiation therapy ( P = O.OOOl), chemotherapy (P = 0.00251, location within the frontal ( P = 0.0034) or parietal lobes (P = 0.0005), and age younger than 60 years (P = 0.0055). Multivariate analysis confirmed the benefit of surgery (P = O.OOOl), radiation therapy ( P = O.OOOl), chemotherapy (P = 0.02881, and younger age (P = 0.05). For patients with single metastases (Table 61, univariate analysis revealed a statistically significant improvement in survival with surgery (P = O.OOOl), radiation therapy (P = 0.0031), and younger age (P = 0.0044). Location within the brainstem (P = 0.0361) and presentation with a generalized seizure (P = 0.0051) had a significant negative impact on survival. Multivariate analysis confirmed a significant improvement in survival with surgery (P = O.OOOl), radiation therapy ( P = 0.0082), and younger age (P = 0.0308), and presentation with a generalized seizure (P = 0.0046).

For patients with single metastases who underwent surgery, presentation with hemorrhage was associated with the shortest survival (median survival, 3 months), and presentation with visual complaints had the best prognosis (median survival, 20 months). Univariate and multivariate analyses demonstrated that adjuvant treatment with radiation therapy significantly improved survival in patients with single metastases who underwent surgery ( P = 0.0002).

DISCUSSION The development of a brain metastasis in the patient with systemic cancer portends a poor prognosis. Without intervention, the median survival after presentation with brain metastases is approximately 1

With treatment with corticosteroids alone, the median survival will increase to 2 month^.'^,'^ In either case, the patient will usually die as a result of their neurologic disease.’ Treatment with WBRT and steroids will prolong the median sur- viva1 to 3 to 6 months.3~5~11~’z~”4-17 With surgical resection of a single brain metastasis, the median survival ranges from 9 to 14 month^.'^^'^-^^ In selected patients, chemotherapy, stereotactic radiosurgery, or resection of multiple metastases may further extend sunriva1.6.20.22-24 Currently, the optimal treatment for brain metastases remains controversial.

As in most reports, the current survival data is confounded by the fact that resection of metastatic disease to the brain is usually reserved for patients with stable systemic disease who are in good neurologic condition. Two prospective randomized trials have demonstrated the benefit of surgery in the

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TABLE 5 The Effect of Tumor Multiplicity and Surgical Intervention on Survival in 729 Patients with Brain Metastases

Factor No. (%) survivala 95% CIb RR P value

Multiplicity 4-6

1.54 0.0001 Single 384 (53) 5 Multiple 345 (47) 3 295-3.01

All lesions 11 8-12

2.17 0.0001 Surgery 171 (24) No surgery 535 (76) 3 2.95-3.01

Single lesions 11 8- 13

2.13 0.0001 Surgety 158 (43) No surgery 210 (57) 3 2-4

Multiple lesions

NS 3-14

1.75 Surgery 13 (4) 6 No surgery 325 (96) 3 2-4

CI: confidence interval; RR: relative risk by Cox proportional hazards ratio; NS: not significant. a Median suMval times in months after presentation with brain metastases. b95% confidence interval for median survival.

TABLE 6 Variable Analysis for Patients with Single Brain Metastases

Univariate Multivariate Variable analysisp RR analysis P RR

Surgery Radiation therapy Chemotherapy Age Location

Frontal Parietal Cerebellum Temporal Occipital Brainstem

Headache Altered mental status Seizure Paresis Gait disturbance Visual complaints Nausealvomiting Dysp hasia Sensory disturbance None

Presenting symptom

0.0001 0.471 0.0031 0.623 0.0131 0.699 0.0044 1.012

NS NS NS NS NS 0.0361 2.543

NS NS 0.0051 0.655 NS NS NS NS NS NS NS

0.0001 0.421 0.0082 0.625 NS 0.0308 1.010

NS NS NS NS NS NS

NS NS 0.0046 0.543 NS NS NS NS NS NS NS

R R relative risk bv Cox orooortional hazards ratio: NS: not simificant

treatment of single metastases.20,25 Patients with or without active systemic cancer and a single brain metastasis who were treated with surgical resection and WBRT had fewer local recurrences, survived longer, and had an improved quality of life compared with patients treated with WBRT A

recent series demonstrated a significant increase in the length of survival for patients who were randomized to either surgery and WBRT or WBRT The benefit of surgery was most pronounced in patients with inactive extracranial disease and in patients who were younger than 60 years of age. For patients with progressive systemic cancer, WBRT alone was as effective as surgery combined with WBRT.25

We have confirmed the benefit of surgery in the treatment of select patients with single metastases to the brain. Surgical resection of a single metastasis in any location except the brainstem was associated with a significant increase in survival. In those patients treated with stereotactic radiosurgery, the median survival was comparable to that of patients with a single lesion who received surgery and WBRT. The fact that there were significant differences in survival times between the different primary tumor types suggests that these differences may be useful in establishing patient prognosis and planning future treatment regimens. One recent trial suggested that there was a difference in survival between patients with lung and nonlung primary tumors metastatic to the brain, although the small number of patients and the grouping of all nonlung tumors together complicated statistical analysis.25 We documented an improved survival in patients younger than 60 years of age; however, it must be remembered that these patients often re- ceive more aggressive therapy than their older counterparts.

In agreement with previous reports based on CT

Brain Metastases/Nussbaum et al. 1787

examination, approximately 50% of our patients had multiple brain meta~tases.~ The true incidence of multiplicity, as determined by autopsy and MR. imaging- based series, may be somewhat higher."-" As reported by others, we found that multiple cerebral lesions were associated with decreased S U T V ~ V ~ ~ ~ . ' ~ * ~ ' * ~ ~ In the setting of multiple metastases, there were only 13 patients in the current series who underwent surgery. These patients had either resection of multiple contig- uous metastases or removal of a single, life-threaten- ing metastasis in the presence of distant lesions that were not resected. The survival times with and without surgery were not significantly different, even though the numbers were too small to allow meaniiigful con- clusions.

Several anecdotal reports have addressed the role of surgery for patients with multiple cerebral m e t a s t a ~ e s . ~ l - ~ ~ In a retrospective study of 56 patients, resection of multiple metastases yielded a median survival time of 14 months, which was comparable to that obtained after resection of a single lesion.6 At the current time, the perforinance of multiple craniotomies for the resection of more than one metastasis is considered a raldical ap- p r o a ~ h . ' ~ Nevertheless, surgery is occasionally considered in the young patient with well controlled systemic disease and brain metastases in (easily accessible locations.6 Alternatively, stereotactic radiosurgery is being increasingly recognized as an important therapeutic modality for the treatment of patients with multiple lesion^."-'^^^^

In conclusion, dissemination of systemic cancer to the brain continues to carry a poor proginosis. Be- cause a variety of therapeutic options, including surgery, WBRT, and stereotactic radiosurgery, are now available, the specific indications for each treatment modality deserve careful attention. Through a better understanding of the natural history of metastatic cancer to the brain, more rational therapeutic regimens may be designed. The metastatic patterns and limited survival associated with certain tumor types may prove useful in directing treatment planning.

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brain metastases: histology, multiplicity, surgery, and survival

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