A randomized trial to assess the efficacy of surgery in addition to radiotherapy in patients with a single cerebral metastasis.

Mintz AH

Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada.

Cerebral metastasis is a common oncologic problem that occurs in 15-30% of cancer patients; approximately half such metastases are single. Previous retrospective studies and two randomized trials reported that the addition of surgical extirpation prior to radiation therapy increased survival, neurologic function, and quality of life compared with radiation alone in patients with a single brain metastasis.A randomized controlled trial was conducted in which patients with a single brain metastasis were allocated to undergo radiation alone or surgery plus radiation. Radiation consisted of 3000 centigray to the whole brain in 10 fractions. RESULTS: Forty-three patients received radiation alone and 41 patients surgery plus radiation. All but two of the study patients died. No difference in survival was detected between the groups; the median survival for the radiation group was 6.3 months compared with 5.6 months for the surgery plus radiation group Most patients died within the first year (69.8% in the radiation arm vs. 87.8% in the surgery plus radiation arm). There were no significant differences in the 30-day mortality, morbidity, or causes of death. Extracranial metastases was an important predictor of mortality (relative risk, 2.3). The mean proportion of days that the Karnofsky performance status was > or = 70% did not differ between the 2 groups. CONCLUSIONS: This trial failed to demonstrate that the addition of surgery to radiation therapy improved outcome of patients with a single brain metastasis. Thus, the efficacy of surgery plus radiation compared with radiation alone needs to be addressed by further clinical trials and/or a meta-analysis.

N Engl J Med 1990 Feb 22;322(8):494-500

A randomized trial of surgery in the treatment of single metastases to the brain.

Patchell RA

Department of Surgery (Neurosurgery Division), University of Kentucky Medical Center

To assess the efficacy of surgical resection of brain metastases from extracranial primary cancer, we randomly assigned patients with a single brain metastasis to either surgical removal of the brain tumor followed by radiotherapy (surgical group) or needle biopsy and radiotherapy (radiation group). Forty-eight patients (25 in the surgical group and 23 in the radiation group) formed the study group; 6 other patients (11 percent) were excluded from the study because on biopsy their lesions proved to be either second primary tumors or inflammatory or infectious processes. Recurrence at the site of the original metastasis was less frequent in the surgical group than in the radiation group (5 of 25 [20 percent] vs. 12 of 23 [52 percent]; P less than 0.02). The overall length of survival was significantly longer in the surgical group (median, 40 weeks vs. 15 weeks in the radiation group; P less than 0.01), and the patients treated with surgery remained functionally independent longer (median, 38 weeks vs. 8 weeks in the radiation group; P less than 0.005). We conclude that patients with cancer and a single metastasis to the brain who receive treatment with surgical resection plus radiotherapy live longer, have fewer recurrences of cancer in the brain, and have a better quality of life than similar patients treated with radiotherapy alone.

Ann Neurol 1993 Jun;33(6):583-90

Treatment of single brain metastasis: radiotherapy alone or combined with neurosurgery?

Vecht CJ,

Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.

The effect of neurosurgical excision plus radiotherapy was compared with radiotherapy alone in a prospectively randomized trial with 63 evaluable patients with systemic cancer and a radiological diagnosis of single brain metastasis. Radiotherapy was given to the whole brain by a novel scheme of 2 fractions per day of each 2 Gy for a total of 40 Gy. Before randomization, patients were stratified by site (lung cancer vs nonlung cancer) and status of extracranial disease (progressive vs stable). Survival as such and functionally independent survival (FIS; defined as World Health Organization performance status < or = 1 and neurological function < or = 1) were compared between both treatment arms. The combined treatment compared with radiotherapy alone led to a longer survival (p = 0.04) and a longer FIS (p = 0.06). This was most pronounced in patients with stable extracranial disease (median survival, 12 vs 7 mo; median FIS, 9 vs 4 mo). Patients with progressive extracranial cancer had a median overall survival of 5 months and a FIS of 2.5 months irrespective of given treatment. Improvement in functional status occurred more rapidly and for longer periods of time after neurosurgical excision and radiotherapy than after radiotherapy alone.

JAMA 1998 Nov 4;280(17):1485-9

Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial.

Patchell RA,

Department of Neurosurgery, University of Kentucky Medical Center

For the treatment of a single metastasis to the brain, surgical resection combined with postoperative radiotherapy is more effective than treatment with radiotherapy alone. However, the efficacy of postoperative radiotherapy after complete surgical resection has not been established.  Ninety-five patients who had single metastases to the brain that were treated with complete surgical resections (as verified by postoperative magnetic resonance imaging) between September 1989 and November 1997 were entered into the study. Patients were randomly assigned to treatment with postoperative whole-brain radiotherapy (radiotherapy group, 49 patients) or no further treatment (observation group, 46 patients) for the brain metastasis, with median follow-up of 48 weeks and 43 weeks, respectively. For patients in the radiation group, radiotherapy was started within 28 days after surgery. Use of corticosteroids was continued without tapering through the first 2 weeks of radiation therapy and then tapered and stopped, if tolerated. The WBRT was given using lateral ports covering the brain and meninges to the foramen magnum. Patients received 50.4 Gy of WBRT over 5 weeks (1.8 Gyx28 fractions) prescribed to the cranial midline. This dose and fractionation scheme were chosen because the total dose was large enough to be effective against micrometastases,and evidence from retrospective datasuggested that low, daily fractionation schemes may result in fewer long-term neuropsychological adverse effects. Recurrence of tumor anywhere in the brain was less frequent in the radiotherapy group than in the observation group (9 [18%] of 49 vs 32 [70%] of 46; P<.001). Postoperative radiotherapy prevented brain recurrence at the site of the original metastasis (5 [10%] of 49 vs 21 [46%] of 46; P<.001) and at other sites in the brain (7 [14%] of 49 vs 17 [37%] of 46; P<.01). Patients in the radiotherapy group were less likely to die of neurologic causes than patients in the observation group (6 [14%] of 43 who died vs 17 [44%] of 39; P=.003). There was no significant difference between the 2 groups in overall length of survival or the length of time that patients remained functionally independent. CONCLUSIONS: Patients with cancer and single metastases to the brain who receive treatment with surgical resection and postoperative radiotherapy have fewer recurrences of cancer in the brain and are less likely to die of neurologic causes than similar patients treated with surgical resection alone.

Am J Clin Oncol 1990 Oct;13(5):427-32

Solitary brain metastasis: results of an RTOG/SWOG protocol evaluation surgery + RT versus RT alone.

Sause WT, Crowley JJ, Morantz R, Rotman M, Mowry PA, Bouzaglou A, Borst JR, Selin H

University of Utah Medical Center, Salt Lake City.

From 1983 through 1986, the Southwest Oncology Group and Radiation Therapy Oncology Group conducted an intergroup study designed to evaluate the effectiveness of surgical resection in those patients with solitary central nervous system (CNS) metastases. The study was initially designed as a prospective randomized trial. Because of difficulty accruing patients, the registration format was altered and the patients were placed on study according to physician preference. Ninety-seven patients were registered on study and 80 patients were eventually analyzed. Fifty-five patients underwent radiation therapy alone and 25 patients received surgery and radiation. Fifty-nine percent of those patients undergoing radiation therapy alone improved or stabilized while 79% of those patients undergoing surgery and radiation therapy improved or stabilized. Eventually, 22% of the surgically treated patients failed in the brain while 45% of the patients undergoing radiation therapy exhibited a CNS relapse. Survival was improved when corrected for other prognostic factors in those patients undergoing surgical resection. Although not a prospective randomized trial, this study does suggest an improvement in the survival of a select group of patients able to tolerate neurosurgical resection.

J Neurosurg 1992 Oct;77(4):531-40

Resection for solitary brain metastasis. Role of adjuvant radiation and prognostic variables in 229 patients.

Smalley SR,

Department of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota.

The authors reviewed 229 consecutive patients treated intramurally by resection of solitary cerebral metastasis. Patients were classified into four groups on the basis of whether a gross total resection or subtotal resection was performed and whether systemic disease was present or absent at the time of craniotomy. Group 1 had gross total resection and no systemic disease; Group 2 had subtotal resection and no systemic disease; Group 3 had subtotal resection and systemic disease; and Group 4 had gross total resection and systemic disease. All four groups were further subdivided into Subgroup A (adjuvant whole-brain radiation therapy) or Subgroup B (no adjuvant radiation). Data were collected regarding multiple patient and tumor variables for multivariate analysis. Survival data for the 46 patients in Group 1A (median 1.3 years, 2-year survival rate 41%, 5-year survival rate 21%) were markedly better than those for the 75 in Group 1B (median 0.7 year, 2-year survival rate 19%, 5-year survival rate 4%). The 20 patients in Group 2A also had superior survival data (median 1.1 years, 2-year survival rate 30%, 3-year survival rate 30%) when compared with the eight patients in Group 2B (median 3 months, 1-year survival rate 0%). However, the 16 and 22 patients in Groups 3A and 4A, respectively, had no discernible differences compared to the seven and 35 patients in their Group 3B and 4B counterparts. Multivariate analyses were performed to assess the association of survival with multiple patient, disease, and treatment variables. Poor neurological status and systemic disease were significantly associated with inferior survival, while longer (greater than 36 months) intervals between primary diagnosis and craniotomy were significantly associated with improved survival. After adjusting for the effects of other patient, disease, and treatment characteristics, adjuvant whole-brain radiotherapy was significantly associated with improved survival times. These data support the continued use of craniotomy followed by adjuvant whole-brain radiation therapy for treatment of solitary brain metastasis. However, this aggressive therapy appears relatively contraindicated in the face of either systemic disease or substantial neurological deficit.

Anticancer Res 2000 Jan-Feb;20(1B):573-7

Significance of surgical resection for the treatment of multiple brain metastases.

Iwadate Y, Namba H, Yamaura A

Department of Neurosurgery, Chiba University, School of Medicine, Japan. i

One hundred and thirty-eight patients who underwent resection for brain metastases and received 30 Gy or more of adjuvant radiation therapy were entered into this study. Seventy-seven of the 138 patients (56%) had single brain metastases (Single Group), while the remaining 61 patients (44%) had multiple foci (Multiple Group). The 138 patients were divided into four subgroups; patients in Single Group treated with total or subtotal resection (Group A), those in Multiple Group who underwent total or subtotal resection and had remaining tumors smaller than 2 cm (Group B), those in Single Group treated with partial resection (Group C), and the other patients in Multiple Group (Group D). RESULTS: The median survival was 8.7 and 9.2 months for the Single Group and the Multiple Group, respectively (not statistically different). The median survival was 9.6, 12.4, 3.7, and 4.5 months for Groups A, B, C, and D, respectively. Survival duration differed significantly between Groups A/B and Groups C/D (p < 0.05). CONCLUSIONS: Surgical reduction of tumor volume which is approximately larger than 2 cm improves the efficacy of adjuvant radiation therapy and contributes to survival even in the patients with multiple brain metastases.

Int J Radiat Oncol Biol Phys 1998 Aug 1;42(1):155-9

Prognostic factors derived from recursive partition analysis (RPA) of Radiation Therapy Oncology Group (RTOG) brain metastases trials applied to surgically resected and irradiated brain metastatic cases.

Agboola O, Benoit B, Cross P, Da Silva V, Esche B, Lesiuk H, Gonsalves C

Cancer Care Ontario, Ottawa Regional Cancer Centre, The University of Ottawa Faculty of Medicine, Canada.

The patients were also grouped into three classes using the RPA-derived prognostic parameters which are: age, performance status, state of the primary disease, and presence or absence of extracranial metastases. Class 1: patients < or = 65 years of age, Karnofsky performance status (KPS) of > or =70, with controlled primary disease and no extracranial metastases; Class 3: patients with KPS < 70. Patients who do not qualify for Class 1 or 3 are grouped as Class 2. The survival of these patients was determined from the time of diagnosis of brain metastases to the time of death. RESULTS: The median survival of the entire group was 9.5 months. The three classes of patients as grouped had median survivals of 14.8, 9.9, and 6.0 months respectively (p=0.0002). Age of < 65 years, KPS of > or = 70, controlled primary disease, absence of extracranial metastases, complete surgical resection of the brain lesion(s) were found to be independent prognostic factors for survival; the total dose of radiation was not. CONCLUSION: Based on the results of this study, the patients and disease characteristics have significant impact on the survival of patients with brain metastases treated with a combination of surgical resection and radiotherapy. These parameters could be used in selecting patients who would benefit most from such treatment.

J Neurosurg 1993 Aug;79(2):210-6

Surgical treatment of multiple brain metastases.

Bindal RK, Sawaya R, Leavens ME, Lee JJ

Department of Neurosurgery, University of Texas M.D. Anderson Cancer Center, Houston.

The authors conducted a retrospective review of the charts of 56 patients who underwent resection for multiple brain metastases. Of these, 30 had one or more lesions left unresected (Group A) and 26 underwent resection of all lesions (Group B). Twenty-six other patients with a single metastasis who underwent resection (Group C) were selected to match Group B by type of primary tumor, time from first diagnosis of cancer to diagnosis of brain metastases, and presence or absence of systemic cancer at the time of surgery. Statistical analysis indicated that Groups A and B were also homogeneous for these prognostic indicators. Median survival duration was 6 months for Group A, 14 months for Group B, and 14 months for Group C. There was a statistically significant difference in survival time between Groups A and B (p = 0.003) and Groups A and C (p = 0.012) but not between Groups B and C (p > 0.5). Brain metastasis recurred in 31% of patients in Group B and in 35% of those in Group C; this difference was not significant (p > 0.5). Symptoms improved after surgery in 65% of patients in Group A, 83% in Group B, and 84% in Group C. Symptoms worsened in 13% of patients in Group A, 6% in Group B, and 0% in Group C. Groups A, B, and C had complication rates per craniotomy of 8%, 9%, and 8%, and 30-day mortality rates of 3%, 4%, and 0%, respectively. Guidelines for management of patients with multiple brain metastases are discussed. The authors conclude that surgical removal of all lesions in selected patients with multiple brain metastases results in significantly increased survival time and gives a prognosis similar to that of patients undergoing surgery for a single metastasis.

Anticancer Res 2000 Jan-Feb;20(1B):573-7

Significance of surgical resection for the treatment of multiple brain metastases.

Iwadate Y, Namba H, Yamaura A

Department of Neurosurgery, Chiba University, School of Medicine, Japan. iwadate@med.m.chiba-u.ac.jp

One hundred and thirty-eight patients who underwent resection for brain metastases and received 30 Gy or more of adjuvant radiation therapy were entered into this study. Seventy-seven of the 138 patients (56%) had single brain metastases (Single Group), while the remaining 61 patients (44%) had multiple foci (Multiple Group). The 138 patients were divided into four subgroups; patients in Single Group treated with total or subtotal resection (Group A), those in Multiple Group who underwent total or subtotal resection and had remaining tumors smaller than 2 cm (Group B), those in Single Group treated with partial resection (Group C), and the other patients in Multiple Group (Group D). RESULTS: The median survival was 8.7 and 9.2 months for the Single Group and the Multiple Group, respectively (not statistically different). The median survival was 9.6, 12.4, 3.7, and 4.5 months for Groups A, B, C, and D, respectively. Survival duration differed significantly between Groups A/B and Groups C/D (p < 0.05). CONCLUSIONS: Surgical reduction of tumor volume which is approximately larger than 2 cm improves the efficacy of adjuvant radiation therapy and contributes to survival even in the patients with multiple brain metastases.

J Clin Oncol 1993 Feb;11(2):369-73

Multiple brain metastases are associated with poor survival in patients treated with surgery and radiotherapy.

Hazuka MB, Burleson WD, Stroud DN, Leonard CE, Lillehei KO, Kinzie JJ

Division of Radiation Oncology, University of Colorado Health Sciences Center, Denver

Between 1980 and 1990, 46 patients underwent surgical resection of brain metastases at the University of Colorado Health Sciences Center. All but two patients received postoperative whole-brain radiotherapy to a median total dose of 30 Gy (range, 11.4 Gy to 50.0 Gy). Lung was the most common (56%) primary site and adenocarcinoma was the most common (46%) tumor histology. Twenty-eight of 46 patients (61%) had solitary metastases, while the remaining 18 patients had two or more foci. RESULTS: The median survival of all 46 patients was 11 months, and the 1- and 2-year survival rates were 40% and 12%, respectively. Moderately severe to severe neurologic impairment at the time of diagnosis and the presence of multiple brain metastases were associated with a significantly poorer survival. In patients with solitary metastasis, gross total resection and adenocarcinoma tumor histology significantly prolonged survival, whereas primary tumor site, the presence of active extracranial disease, and radiation dose had no significant effect on survival. CONCLUSION: These results are consistent with a recent randomized study supporting the role of surgery and whole-brain radiation therapy in the management of patients with solitary brain metastases. We would caution against the generalization of this concept to patients with two or more brain metastases.