Management strategies for patients with brain metastases: has radiosurgery made a difference?

Background: Brain metastases develop in up to 50% of all patients with cancer. The purpose of this retrospective study was to compare the outcomes for brain metastases patients treated with adjuvant whole-brain radiotherapy (WBRT) or stereotactic radiosurgery (SRS).

Methods: Between 1990 and 1995, 86 patients with brain metastases received external beam WBRT with a megavoltage beam at our center. Between January 2000 and July 2001, 48 patients with 84 tumors diagnosed as cerebral metastases were treated with SRS using the Leksell Gamma Knife. A comparative analysis of the outcomes in the two different groups was made to determine a possible statistically significant difference in survival.

Results: In the WBRT group, the median follow-up was 11 months. Thirty-nine patients (45.3%) experienced an improvement in neurologic status. The median overall survival was 5 months (range, 1-40 months). In the SRS group, the median follow-up for this group was 9 months. Thirty-four patients experienced an improvement in their neurologic signs and symptoms. The median survival was 12 months (range, 1-16 months).

Conclusion: SRS appears to be a safe and effective treatment option for those patients with a limited number of brain metastases and in patients with controlled or limited systemic disease.

Key Words: brain metastases, radiation therapy, radiosurgery, resection

**********

Brain metastases develop in up to 50% of all patients with cancer. (1) Recent studies show that in the United States between 80,000 and 170,000 individuals develop brain metastases each year. (2) Thus, it becomes imperative that as we continue to make advancements in the treatment and palliation of systemic disease, we make simultaneous advancements in the management of intracranial disease, particularly in those patients in whom minimal or no systemic disease is demonstrated. The main purpose of the treatment is to reverse the patient's neurologic deficits and prolong life. Nevertheless, opinions remain divided on whether meaningful clinical progress has been achieved overall. (2) A clinician working in a tertiary referral center offering radiosurgery for a select group of patients may believe that the therapeutic nihilism of the past is no longer warranted, whereas another, whose experience is based on the management of patients dying from metastatic cancer, may still question the value of active treatment. Several options exist for the treatment of single and multiple brain metastases, and the success of each is strongly influenced by several factors such as tumor location, number of metastases, functional level of the patient, and histologic type of primary tumor. (1) The purpose of this retrospective study was to compare the outcomes for brain metastases patients treated with whole-brain radiotherapy (WBRT) and stereotactic radiosurgery (SRS). Recommendations will then be made regarding the optimal treatment of patients with brain metastases, not only to control the disease but also to provide the optimal quality of life and function.

Methods

Between 1990 and 1995, 86 patients with 130 brain metastases received external beam radiotherapy with a megavoltage beam at Louisiana State University Health Sciences Center in Shreveport, Louisiana. A fraction size of 3 Gy was used and a midplane dose of 30 Gy in 10 fractions was delivered using the Clinac 6-100 LINAC (Varian, Inc., Palo Alto, CA). The age range of the patients was 25 to 78 years (mean, 58 years). Twenty-eight (32.6%) were females and 58 (67.4%) were males. Lung (70%) was the most common primary site for the cancer, followed by breast (12.8%) and melanoma (3.5%). Forty-two patients (48.8%) had solitary tumors, whereas 44 (51.2%) had multiple metastases. Of the 42 patients with solitary tumors, all had previous excision. Twenty-six patients had local recurrence after complete excision, and the other 16 patients developed tumors at a different site than the previous excision. The Karnofsky Performance Scale score varied from 60 to 90 (mean, 80).

The Leksell Gamma Knife was acquired by the Department of Neurosurgery at the Louisiana State University Health Sciences Center in Shreveport in January 2000. Between January 2000 and July 2001, 48 patients with 84 tumors diagnosed as cerebral metastases were treated with stereotactic radiosurgery using the Leksell Gamma Knife. The mean patient age was 56 years (range, 36-81 years). Lung carcinoma (54.2%) was the most common primary tumor, followed by breast (14.6%) and melanoma (14.6%). The mean Karnofsky Performance Scale score of the patients was 90 (range, 70-100). Twenty patients (41.7%) had solitary metastases, whereas 28 (58.3%) had multiple tumors. Radiosurgery dose planning was performed using the Leksell Gamma Plan software version 5.3 (Elekta Instruments, Atlanta, GA) by a team consisting of a neurosurgeon, a radiation oncologist, and a medical physicist. The mean marginal dose prescription to the tumor was 16 Gy (range, 13-19 Gy). A 50% isodose line was used in all cases to conform the dose to the tumor margins. Radiosurgery was then administered using the Leksell Gamma Knife model "B-2" (Elekta Instruments). A comparison of the demographic data for the patients in these two groups is shown in Table 1. The radiologic and clinical follow-up outcomes were compiled for patients in both the above-stated groups retrospectively.

Statistical Analysis

The overall survival and the brain-disease control rates for both groups were calculated using the method of Kaplan and Meier. A comparative analysis of the overall survival and brain disease-free survival rates in the two groups was conducted using the log-rank test and Breslow's test, which determined a possible statistically significant difference in survival between the patients of both groups. A value of P < 0.05 was considered statistically significant.

Results

WBRT Group

The median follow-up for the patients in this group was 11 months. At last follow-up, 2 patients were alive and 84 had died. Fifty-two deaths (61.9%) occurred as a result of progressive brain disease, whereas 32 patients (38.1%) died due to systemic disease. Thirty-nine patients (45.3%) experienced an improvement in neurologic status detected on follow-up clinic visits. The mean overall survival in this group was 13 months (range, 1-40 months) and the median survival was 5 months. The actuarial overall survival for patients in this group calculated by the Kaplan-Meier method was 45.5 [+ or -] 0.5% at 6 months and 23.11 [+ or -] 0.5% at 12 months (95% confidence interval) (Figs. 1 and 2).

SRS Group

The median follow-up for this group was 9 months. At last follow-up, 23 patients were alive and 25 had died. Fourteen (56%) deaths were a direct result of progressive brain disease. Clinically, 34 patients (70.8%) experienced an improvement in their neurologic signs and symptoms. Local control was defined as no tumor growth (with caliper measurement) and no increase in clinical symptoms associated with the lesion. Sixty-four (77.1%) of the 84 treated tumors were controlled with radiosurgery, whereas 20 continued to progress. The mean overall survival was 8 months (range, 1-16 months) and median survival was 12 months (95% confidence interval). The actuarial 6-month and 12-month survival rates for this group were 64.7 [+ or -] 0.9% and 42.3 [+ or -] 1.2%, respectively. Table 2 depicts a comparison of the outcomes for patients in the two groups. A statistical analysis revealed that the group that received stereotactic radiosurgery had statistically significant clinical improvement (P = 0.03) and median brain disease-free survival (P = 0.0016). Also, the number of patients dying from the metastatic brain disease was significantly reduced in the group receiving stereotactic radiosurgery (P = 0.0007).

[FIGURE 1 OMITTED]

Discussion

The diagnosis of brain metastases in a cancer patient is frequently made and has been associated with a dismal prognosis. Although more patients harbor multiple rather than solitary tumors at presentation, few gains have been made in the treatment of this disease. Historically, the two treatment options that have existed for the patients have included radiotherapy and surgical resection. (3-7) In their prospective randomized trials, Patchell et al (6) and Vecht et al (7) both reported that surgical resection plus radiotherapy showed better tumor control and survival than radiotherapy alone. In another trial, Mintz et al (8) found no survival benefit in patients treated with surgical resection plus WBRT versus WBRT alone. It is significant to note that in this study by Mintz et al, the patients studied had more progressive systemic disease, thus possibly accounting for the lack of benefit associated with resection. Despite the improved survival afforded by resection, there are limitations to its use. Furthermore, because many patients have metastases in brain locations not amenable to surgical resection, the potential benefit of resection cannot be offered to all patients. Thus, presenting functional status of the patients significantly influences the effectiveness of WBRT.

[FIGURE 2 OMITTED]

WBRT alone has also not proved to be universally effective in prolonging survival or achieving definite control of the cerebral metastases in patients with cancer. (7) The normal dose of 30 Gy in 10 to 12 fractions for WBRT was reported to show no improvement in survival in patients with metastatic disease to the brain. (9,10) Patchell et al (6) reported a recurrence rate of >80% when WBRT is used alone for the treatment of solitary brain metastasis. The trial of Noordjik et al (5) included more patients with active systemic disease, and yet did not find a survival benefit of combining surgical resection with WBRT in patients with solitary brain metastasis. In the present series, the patients undergoing WBRT with or without surgery had a median survival of 5 months, which is consistent with most of the previous published series. The number of metastases (solitary versus multiple) did not influence the survival for these patients (P = 0.62).

SRS has been established as an important adjuvant in the treatment of cerebral metastases. Unlike surgical resection, which is difficult to perform with more than one tumor, the number of metastases treated with SRS is limited only by the patience of the treating team. Most centers are comfortable treating patients with up to six tumors in one sitting. (11) At our center, we have treated patients with up to nine tumors in a single session, but we usually try to limit ourselves to treating patients with up to five metastases. The median survival of patients receiving gamma knife radiosurgery in our series was 12 months, which is almost double the survival time in the WBRT group (P = 0.0016) (Fig. 2). In addition, 71% of our patients showed neurologic improvement and hence had a better quality of life after radiosurgery (P = 0.03). Also noteworthy is the fact that the majority of the patients in this group (70%) died from systemic disease rather than from the brain tumors (P = 0.0007) (Table 2).

These results are congruent with most of the larger series. A multi-institutional study from the Gamma Knife Users Group of 116 patients with solitary tumors treated with the gamma knife found median survival to be 11 months after radiosurgery. (11) Auchter et al (12) studied 122 patients with potentially resectable tumors that were treated instead with radiosurgery. Median survival was 14 months. Table 3 depicts the results for radiosurgery in patients with brain metastases in representative series.

Benefits of Gamma Knife Stereotactic Radiosurgery

Extended survival is only one of the benefits of radiosurgery compared with WBRT and surgical resection. The minimally invasive nature of the procedure makes radiosurgery much less likely to cause the residual side effects characteristic of radiotherapy. (2) Another specific use for radiosurgery is in histologic types not sensitive to radiotherapy, such as renal cell carcinoma and melanoma. In these patients, radiosurgery is significantly more effective than WBRT in extending survival and minimizing side effects of treatment. (11) Another minor but important issue frequently being discussed in this age of "managed health care" is that of the cost-effectiveness of any procedure. Stereotactic radiosurgery has been established to be as cost-effective (if not more) as the other modalities of treatment. A comparison published by the Gamma Knife Users Group showed that the average cost per resection is $30,461 versus $22,743 for radiosurgery. (11)

A further item of debate is whether or not to follow radiosurgical treatment with WBRT. We believe that radiosurgery alone is the optimal treatment for patients with both solitary and multiple metastases to the brain. The authors at this institution have already initiated a prospective, randomized trial to assess the benefits of radiosurgery alone in the treatment of patients with three or fewer cerebral metastases from a known primary location (institutional review board No. H00159), and the early results are expected to be available at the end of this year.

Therefore, the diagnosis of metastatic disease to the brain is no longer an immediate death warrant. With the advent of radiosurgery, it appears that survival is not solely determined by intracerebral disease. The ability to halt progression of cancer in the brain, while maintaining functional capacity and quality of life, has become a primary concern in the battle against cancer. By prolonging life in this aspect, attention can be focused on managing the systemic state of the patient, as this factor will ultimately determine the length of survival. (3,10)

Conclusion

On the basis of our own experience and that published in the literature, we suggest that gamma knife stereotactic radiosurgery appears to be a very safe and effective treatment option for those patients with a limited number of brain metastases and in patients with controlled or limited systemic disease. Thus, this is a treatment option that could benefit a large percentage of patients. The key now is education and utilization. Radiosurgical treatment options are available, and patients should be informed of this option and evaluated for possible treatment. Prospective randomized trials from more than one institution are needed to ascertain the benefits of additional WBRT with radiosurgery in the management of patients with solitary or a limited number of brain metastases.

Table 1. Comparison of Patient Demographics for WBRT and SRS Groups (a)

Characteristic    WBRT group              SRS group

Age
  Range           25-78                   36-81
  Mean            58                      56
M:F (%)           67.4:32.6               54.1:45.2
Common primaries  Lung, breast, melanoma  Lung, breast, melanoma
KPS
  Range           60-90                   70-90
  Mean            80                      80

(a) WBRT, whole-brain radiation therapy; SRS, stereotactic radiosurgery;
KPS, Karnofsky Performance Scale.

Table 2. Statistical analysis of the outcome at-a-glance for the
patients with brain metastases treated with WBRT or SRS (a)

                      WBRT                  SRS
Outcome               Group                Group               P value

Clinical improvement  45.3%                70.1%               0.03
Survival (mo)                                                  0.0016
  Median               5                   12
  Range                1-40                 1-16
Deaths from brain     60.4%                29%                 0.0007
  disease
Actuarial 6-mo
  survival            45.5 [+ or -] 0.5%   64.7 [+ or -] 0.9%  0.12
  (Kaplan-Meier)
Actuarial 12-mo
  survival            23.11 [+ or -] 0.5%  42.3 [+ or -] 1.2%  0.056
  (Kaplan-Meier)

(a) WBRT, whole-brain radiation therapy; SRS, stereotactic radiosurgery.

Table 3. Results of radiosurgery for the brain metastases in different
series

                           No. of      Dose         Local
Institution               patients  margin (Gy)  control (%)

University of Pittsburgh     77        16            85
Harvard JCRT                248        15            83
UCSF                        119        18.5          93
Karolinska                  160        30            94
LSUHSC-S                     48        16            77

                                           Median
Institution               Necrosis (%)  survival (mo)

University of Pittsburgh       4             10
Harvard JCRT                   3              9
UCSF                           4             11
Karolinska                     NS            NS
LSUHSC-S                       6.2           12

(a) JCRT, Joint Center for Radiation Therapy; UCSF, University of
California, San Francisco; LSUHSC-S, Louisiana State University Health
Sciences Center in Shreveport; NS, not stated.

Accepted December 10, 2002.

Copyright [c] 2004 by The Southern Medical Association

0038-4348/04/9703-0254

References

1. Kondziolka D, Patel A, Lunsford LD, et al. Decision making for patients with multiple brain metastases: Radiosurgery, radiotherapy, or resection? Neurosurg Focus 2000;9:1-6.

2. Thomas G. Brain metastases, in Thomas G (ed). Current Problems in Cancer Brain Metastases. St. Louis, Mosby, 1989, pp 55-98.

3. Borgelt B, Gelber R, Kramer S, et al. The palliation of brain metastases: Final results of the first two studies by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 1980;6:1-9.

4. Cho K, Hall WA, Gerbi BJ, et al. The role of radiosurgery for multiple brain metastases. Neurosurg Focus 2000;9:1-7.

5. Noordjik EM, Vecht CJ, Haaxma-Reiche H, et al. The choice of treatment of single brain metastasis should be based on extracranial tumor activity and age. Int J Radiat Oncol Biol Phys 1994;29:711-717.

6. 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.

7. Vecht CJ, Haaxma-Reiche H, Noordjik EM, et al. Treatment of single brain metastasis: Radiotherapy alone or combined with neurosurgery? Ann Neurol 1993;33:583-590.

8. 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.

9. Kondziolka D, Lunsford LD, Flickinger JC. Gamma knife radiosurgery for brain metastases, in Germano I (ed): LINAC and Gamma Knife Radiosurgery for Brain Metastases. Park Ridge, IL, AANS, 1999, pp 167-176.

10. Smalley SR, Schray MF, Laws ER Jr, et al. Adjuvant radiation therapy after surgical resection of solitary brain metastasis: Association with patterns of failure and survival. Int J Radiat Oncol Biol Phys 1987;43:1611-1616.

11. Flickinger JC, Kondziolka D, Lunsford LD. Radiosurgery management of brain metastasis from systemic cancer, in Flickinger JC, Kondziolka D, Lunsford LD (eds): Gamma Knife Brain Surgery. New York, Karger, 1998, pp 145-159.

12. Auchter RM, Lamond JP, Alexander E, et al. A multiinstitutional outcome and prognostic factor analysis of radiosurgery for respectable single brain metastasis. Int J Radiat Oncol Biol Phys 1996;35:27-35.

RELATED ARTICLE: Key Points

* The ability to halt progression of cancer in the brain, while still maintaining functional capacity and quality of life, has become a primary concern in the battle against cancer.

* The purpose of this retrospective study was to compare the outcomes for brain metastases patients treated with whole-brain radiation therapy or stereotactic radiosurgery as the primary modality or as an adjuvant to prior surgery.

* Gamma knife stereotactic radiosurgery appears to be a safe and effective treatment option for those patients with a limited number of brain metastases and in patients with controlled or limited systemic disease.

Ajay Jawahar, MD, Federico Ampil, MD, Christina Wielbaecher, BS, Golda H. Hartman, BS, John H. Zhang, MD, PHD, and Anil Nanda, MD

From the Departments of Neurosurgery and Radiation Oncology, Louisiana State University Health Sciences Center in Shreveport, Shreveport, LA.

Reprint requests to Anil Nanda, MD, FACS, Department of Neurosurgery, Louisiana State University Health Sciences Center in Shreveport, 1501 Kings Highway, P.O. Box 33932, Shreveport, LA 71130-3932. Email: [e-mail]