Gamma knife-based stereotactic radiosurgery boost after whole-brain radiotherapy in patients with up to three brain metastases: Effects on survival, functional independence, and neurocognitive function

Sankalp Singh; Arti Sarin; Manoj Semwal; Sharad Bhatnagar; Maneet Gill; Shweta Sharma

doi:10.4103/IJNO.IJNO_14_19

ORIGINAL ARTICLE

Year : 2019 | Volume : 2 | Issue : 2 | Page : 101-111

Gamma knife-based stereotactic radiosurgery boost after whole-brain radiotherapy in patients with up to three brain metastases: Effects on survival, functional independence, and neurocognitive function

Sankalp Singh¹, Arti Sarin², Manoj Semwal³, Sharad Bhatnagar⁴, Maneet Gill⁵, Shweta Sharma⁶
¹ Department of Radiation Oncology, Command Hospital (CC), Lucknow, Uttar Pradesh, India
² Department of Radiation Oncology, INHS Asvini, Mumbai, Maharashtra, India
³ Department of Radiation Oncology and Medical Physicist, Army Hospital (R&R), New Delhi, India
⁴ Department of Radiation Oncology, Army Hospital (R&R), New Delhi, India
⁵ Department of Neurosurgery, Army Hospital (R&R), New Delhi, India
⁶ Department of Radiation Oncology, Narayana Superspeciality Hospital, Kolkata, West Bengal, India

Date of Submission	11-Sep-2019
Date of Acceptance	03-Nov-2019
Date of Web Publication	10-Jan-2020

Correspondence Address:
Dr. Arti Sarin
INHS Asvini, Mumbai, Maharashtra
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IJNO.IJNO_14_19

Abstract

Background: Brain metastases are a major cause of mortality and morbidity in cancer patients and are seen as a terminal event in the natural course of disease. Whole-brain radiotherapy (WBRT) has remained the most commonly used treatment for multiple metastases. Although it provides symptomatic relief, the effects have low durability and local failure is common. Stereotactic radiosurgery (SRS) techniques such as Gamma Knife have been shown to be as effective as surgery in control of limited (1–3) metastases.
Aim: The aim of this is to study the role of SRS boost after WBRT in patients of 1–3 brain metastases.
Objective: (1) To compare the survival of patients with 1–3 brain metastases treated with WBRT with versus without SRS boost. (2) To compare the duration of functional independence (FI) and normal neurocognitive function (NNF) posttreatment in the patients belonging to the two groups.
Materials and Methods: Twenty-six patients with 1–3 brain metastases received WBRT to a dose of 30 Gy in 10 fractions. Half the patients (13) were also given an SRS boost of 16–20 Gy by the Gamma Knife technique. All patients were followed up at twelve weekly intervals for a period of 9 months and assessed for survival, FI (Karnofsky Performance Status Score (KPS) >60%) and NNF (Hindi Mental Status Examination Score >24).
Results: At 9 months, the median survival in the SRS boost group was 27 weeks compared to 22 weeks in the no boost group. The mean duration of FI and NNF was 24 and 12 weeks in the boost and nonboost groups, respectively. The differences between two groups were not statistically significant.
Conclusions: Although results are not significant, a definite trend toward improvement in median survival, FI, and neurocognitive function in patients who received an SRS boost after WBRT is seen.

Keywords: Brain metastases, gamma-knife surgery, stereotactic radiosurgery, whole-brain radiotherapy

How to cite this article:
Singh S, Sarin A, Semwal M, Bhatnagar S, Gill M, Sharma S. Gamma knife-based stereotactic radiosurgery boost after whole-brain radiotherapy in patients with up to three brain metastases: Effects on survival, functional independence, and neurocognitive function. Int J Neurooncol 2019;2:101-11

How to cite this URL:
Singh S, Sarin A, Semwal M, Bhatnagar S, Gill M, Sharma S. Gamma knife-based stereotactic radiosurgery boost after whole-brain radiotherapy in patients with up to three brain metastases: Effects on survival, functional independence, and neurocognitive function. Int J Neurooncol [serial online] 2019 [cited 2023 Mar 25];2:101-11. Available from: https://www.Internationaljneurooncology.com/text.asp?2019/2/2/101/275531

Introduction

Brain metastases are the most common form of brain cancer. They outnumber primary brain tumors by a factor of 10-1. Since no national cancer registry documents brain metastases, the exact incidence is unknown; however, autopsy series demonstrate an incidence rate of 10%–30% for all patients with a diagnosis of cancer. The most common primary cancers metastasizing to the brain are lung cancer (50%), breast cancer (15%–20%), unknown primary cancer (10%–15%), melanoma (10%), and colon cancer (5%).^[1]

During the computed tomography (CT) era as many as 50% of patients with tumor metastatic to the brain were found to have a single metastasis. However, data acquired with modern CT and magnetic resonance imaging (MRI) technology indicate that about 20% of patients thought to have a single brain metastasis based on CT actually have multiple lesions on MRI.^[2] The incidence of brain metastases seems to have increased over the past decade, and this may be the paradoxical result of the effectiveness of systemic drugs that do not cross the blood–brain barrier. As a result of the increased survival in patients receiving chemotherapy, brain metastases may become symptomatic.^[3] The greater availability and use of MRI, which is now the gold standard for the detection of brain metastases,^[4] has also had a role in the increase in the incidence of brain metastases.^[1] Brain metastases most commonly present with neurologic signs and symptoms and are a significant cause of neurologic morbidity in cancer patients.

Prognosis and prognostic indices

Overall median survival of a patient with symptomatic brain metastases, undergoing treatment for the same, is said to be <1 year, and often ranging between 4 and 6 months, though this figure represents an extremely heterogeneous group of patients. A number of independent prognostic factors need to be estimated to further classify such patients into subsets and to enable the clinician to decide between invasive treatments and to avoid unnecessary treatment. Demographic and clinical variables that might be of prognostic significance for brain metastases have been analyzed extensively and include age, performance status (often determined by the use of the Karnofsky Performance Status Score), type of primary tumor (e.g. lung or breast), number of brain metastases (single or multiple), and the extent and status of extracranial disease.^[5],[6] Findings on brain imaging may also serve as prognostic factors, such as the number of metastases, presence of midline shift, and postwhole-brain radiotherapy (WBRT) response, can also influence outcome.^[7],[8] Thus, several prognostic indices such as recursive partition analysis (RPA),^[5],[9] as shown in [Table 1], score index for radiosurgery and graded prognostic Analysis (GPA) index have been described. In a more recent analysis, Sperduto et al.^[10] carried out a retrospective analysis of 5067 brain metastases patients and found that the effect of prognosis factors on outcome varied by the diagnosis of primary disease. Thus, a disease-specific classification of outcomes as per prognostic factors was proposed called the Diagnosis-Specific GPA.

Table 1: Prognostic factors by recursive partition analysis class

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Even though it is common for patients with multiple brain metastases to have active primary and other systemic metastatic disease, progression of brain disease is the cause of death in about half of these patients (range, 26%–70%).^[11]

Treatment options

The four main modes of therapy include surgery, stereotactic radiosurgery (SRS), whole-brain radiation therapy (WBRT), and supportive care only. Young patients with limited extracranial disease may benefit from surgical resection of a single brain metastases, and from radiosurgery (or stereotactic radiotherapy). Whether WBRT after surgery or radiosurgery is beneficial is debatable. Therefore, two approaches can be justified in patients with a good prognosis: WBRT after surgery or radiosurgery, or alternatively, observation with MRI follow-up after surgery or radiosurgery. Patients with multiple brain metastases (>4) and/or extensive extracranial tumor activity are usually treated with WBRT alone.

Surgery

Surgical resection can provide immediate relief of the tumor mass effect. On the other hand, radiation generally takes several days to work. There have now been three phase III trials testing the hypothesis that surgical resection to single brain metastasis is potentially beneficial.^{[12],[13],[14]} The results of these studies suggest that surgical resection should be reserved for patients with a solitary metastasis and good performance status (i.e., KPS ≥70) or those patients with multiple lesions causing life-threatening complications due to mass and pressure effects.

Whole-brain radiotherapy

WBRT continues to be the standard of care in patients with brain metastasis. In general, WBRT should be given soon after the diagnosis of brain metastasis. There has never been any evidence to suggest that delaying systemic chemotherapy for WBRT compromises overall survival, especially when one considers that progression in the brain frequently leads directly to the death of the patient.^[15]

There is still no agreement on the dose and fractionation schedule for WBRT despite numerous studies designed to determine the optimum delivery. A total of 30 Gy in 10 fractions continues to be the standard for most patients. In chemotherapy-refractory, RPA Class III patients, a shorter fractionation scheme (e.g., 20 Gy in five fractions) should be considered. However, short fractionation schemes should be avoided in chemotherapy-naive patients with brain metastasis as the presenting event in the cancer diagnosis. The natural disease course of such patients can be frequently unpredictable, and hence, they may live sufficiently long enough to experience late radiation toxicity posed by such short fractionation schedules.^[16]

Stereotactic radiosurgery

Radiosurgery provides a substitute or alternative to conventional surgery in the setting of single brain metastasis. Although no randomized trials have been performed comparing surgery with SRS, the latter appears to provide similar local control rates (80%–90% when combined with WBRT). Unless the tumor causes significant edema and mass effect, with consequent hydrocephalus or herniation requiring urgent surgical intervention, SRS can serve as a noninvasive alternative. Frequently, a patient may not be a craniotomy candidate because of tumor location in eloquent areas or existing medical contraindications and can be offered SRS.^[12] While there clearly is a role for SRS in a single brain metastasis;^[17] however, there is no clear evidence of any advantage of using SRS over WBRT in the clinical setting of multiple brain metastases.

Brain metastases are ideal targets for radiosurgery. The tumors are often spherical, with a diameter of <3 cm, and have radiographically distinct margins. They are, therefore, well compatible with dose distributions, with a rapid fall-off of radiation dose at the edge of the target volume delivered by the gamma knife or linear accelerator.^[18]

SRS is highly effective even for brain metastases that are otherwise resistant to conventional fractionated external-beam radiation therapy. The Gamma Knife principle is based on the mechanical focusing of 201 radiation sources, resulting in an extremely limited irradiated volume. By the addition of several focuses (isocenters), virtually any geometrical structure can be matched, thereby allowing the exclusive irradiation of the target within the brain, i.e., the metastases in the current context. Gamma Knife treatment is carried out in one session (1 day) under local anesthesia and causes low physical stress to the patient. The necessary precision requires a stereotactic frame fixation, a stereotactic MRI study, treatment planning, and execution. In general, prescription doses of 18–22 Gy are applied in Gamma Knife treatment of cerebral metastases. Doses are expressed as “minimum” or “prescription doses,” reflecting the dose applied to the tumor periphery. This very often corresponds to the 50% isodose, resulting in an inhomogeneous dose distribution within the tumor, with a maximum dose ranging between 36 and 50 Gy.^[19]

Neurocognitive decline in patients of brain tumors

Historically, brain radiation has been frequently cited as the major cause of the neurocognitive decline in cancer patients and an 11% risk of radiation-induced dementia was reported by DeAngelis et al. in their study based on the Memorial Sloan-Kettering experience.^[16] However, this study is considered one of the most misinterpreted on this subject^[15] and in a separate study by DeAngelis et al. of a larger cohort a more accurate risk of about 2%–5% has been reported.^[20] This risk is offset by the potentially life-prolonging advantage of WBRT.

There are now strong data that other factors, such as anticonvulsants, benzodiazepines, opioids, chemotherapy, craniotomy, and most importantly, the brain tumor, contribute significantly to the neurocognitive decline of patients with brain tumor.^[21] In fact, WBRT may actually improve neurocognition in a significant number of patients, as brain recurrence or progression, which are associated with a decrease in neurocognitive function,^[22] are prevented by WBRT.

Aim and objectives

The aim of our study was to evaluate any advantage of using the SRS boost after WBRT in patients of 1-3 brain metastases in the Indian population.

The objectives of our study were as follows:

Primary: To compare the survival of patients with 1–3 brain metastases treated with WBRT plus SRS boost versus those treated with WBRT alone in the Indian population
Secondary: To compare the duration of functional independence (FI) and normal neurocognitive function (NNF) posttreatment in patients belonging to the two groups.

Materials and Methods

This was a prospective comparative study conducted at a tertiary care cancer center of India, over a period of 2 years after approval from the Institutional Ethical Committee. Informed consent from all the study participants was obtained. The study participants were patients of histologically proven solid malignancies with 1-3 brain metastases. Only patients in the age group between 18 and 70 years with the Karnofsky performance status score of 70% or more and an RPA stratification of class 1 or 2 were included in the study. Patients were assessed for the neurocognitive function using the Hindi language version of the Mini mental state examination (MMSE) called the Hindi mental state examination (HMSE) [Figure 1] and patients had to have a minimum score of 24 to be included in the study. Like the MMSE, the HMSE is a questionnaire which allocates points for correct answers. The maximum score is 31 and a score of 23 is used as a cutoff for cognitive dysfunction or dementia. The HMSE maybe better suited for neurocognitive testing of the largely Hindi-speaking Indian population.^[23] The brain lesions had to be diagnosed on a baseline MRI and had to be suitable for GKS. Hence, lesions >3 cm in size, those involving the brainstem or those at a distance of <5 mm were not included in the study.

Figure 1: Hindi mental scale examination

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Patient and disease variables such as age (<60 or ≥ 60 years), gender, diagnosis of primary cancer, number of brain metastases, size of largest brain metastases, KPS, HMSE score, RPA class, and status of extracranial disease (controlled or uncontrolled), were recorded at presentation.

The standard of care at our center for a patient with brain metastases without pressure symptoms (in which case the patient undergoes surgery) is WBRT alone. For the first 6 months of the patient accrual, the same treatment protocol was followed with all patients (Group 1) receiving a dose of 30 Gy in 10 fractions on a Primus Linear Accelerator. Patients accrued in the next 6 months (Group 2) were treated with WBRT followed by an SRS boost on a Leksell Gamma Knife 4C machine to a dose between 16 and 24 Gy in a single sitting at 4 weeks after the completion of WBRT.

All patients underwent twelve weekly follow-up for a minimum period of 36 weeks (9 months) or till death whichever was earlier. At each follow-up, the patients were assessed for survival, FI, and neurocognitive function. A patient was said to be functionally independent if he had a KPS of 60% or more, while he was deemed to have NNF if he had an HMSE score of 24 or more. For patients who died, it was attempted to classify them into death due to cranial or extracranial causes. The death was considered to be due to cranial disease if the patient died due to the progression or worsening of neurological symptoms, whereas if he died due to complications of nonneurological symptoms, he was deemed to have died of extracranial disease.

The entire statistical analysis was performed using IBM Statistical Package for social sciences (SPSS) version 17 (International Business Machines Corporation (IBM), Armonk, New York, U.S.). The median period of survival, FI, and NNF was estimated using Kaplan–Meier method and compared in the two groups by stratified Log-rank test. Percentage of patients who were alive, functionally independent and had normal neurocognitive functional 12, 24, and 36 weeks were measured and compared in the two groups. Association between different patient, disease and treatment parameters was assessed using the Chi-square test or Fisher's exact test as appropriate. Five percent probability level (allowing an α error of 5%) was considered as statistically significant, i.e., P< 0.05. Prognostic value of RPA, primary malignancy and number of brain metastases in predicting survival of patient was compared in the two groups. Cranial versus extracranial cause of death in the two groups was also compared though nonstatistically.

Results

A total of 71 patients of brain metastases presented to our center during the study accrual period; however, only a total of 26 patients fulfilled the inclusion criteria and were selected for the study. The first 13 patients were included in Group 1 (WBRT), whereas the next 13 were included in Group 2 (WBRT + SRS). The frequency of various parameters in the study group is shown in [Table 2]. The range and median of descriptive parameters are displayed in [Table 3].

Table 2: Frequency table of the study group

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Table 3: Descriptive parameters of the study group

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Twenty-one patients completed the study, with 5 patients being lost to follow-up. For the purposes of statistical analysis, 10 patients were considered in Group 1 and 11 in Group 2. There was no statistically significant difference in the distribution of qualitative predetermined study variables such as sex, age group, RPA class, number of brain metastases, and extracranial disease status in the two groups. There was also no statistically significant difference in the baseline scores KPS and HMSE scores showing that the patients were uniformly stratified in the two groups with respect to the performance status and neurocognitive status.

Survival

On comparison of survival in the two groups by the Log-Rank test, it was seen that median survival in Group 1 was 22 weeks (5.5 months) compared to 27 weeks (6.75 months) in Group 2 [Table 4] and [Figure 2]a. This difference in median survival of 5 weeks (1.25 months) was not found to be statistically significant (P = 0.414). The percentage of patients surviving at 12, 24, and 36 weeks in the two groups is shown in the graph in [Figure 3]a. Although the study follow-up was till 36 weeks only, patients who survived beyond this period were continued to be followed up, though this data were not included in the final analysis. The highest survival seen till the completion of the study was 60 weeks (15 months) in Group 1 and 44 weeks (11 months) in Group 2. The patient in Group 1 had died, but the one in Group 2 was still alive at the time of completion of the study.

Table 4: Survival, functional independence, neurocognitive function, and death due to neurological progression

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Figure 2: Kaplan–Meier curves comparing study outcomes at 12, 24, and 36 weeks between Group 1 (Whole-brain radiotherapy) and Group 2 (whole-brain radiotherapy + stereotactic radiosurgery). (a) Comparison of survival at 12, 24 and 36 weeks in the two treatment groups. (b) Comparison of functional independence at 12, 24 and 36 weeks in the two treatment groups. (c) Comparison of normal neurocognitive function at 12, 24 and 36 weeks in the two treatment groups

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Figure 3: Graphs showing percentage of patients with different treatment outcomes in the two treatment groups at 12, 24, and 36 weeks. (a) Percentage of surviving patients recorded at 12 weekly intervals in the 2 arms. (b) Percentage of total patients in 2 arms whoremained functionally independent at 12 weekly follow up in the 2 arms. (c) Percentage of total patients in the 2 arms who maintained normal neuroccognitive function

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Functional independence

The median period of FI at 36 weeks for all patients in the study was estimated as 12 weeks by the Kaplan–Meier method. On comparison of the two groups by Log-Rank test, we see that median period of FI in Group 1 was 12 weeks (3 months) compared to 24 weeks (6 months) in Group 2 [Table 4] and [Figure 2]b. This difference of 12 weeks (3 months) was not found to be statistically significant (P = 0.477). The percentage of patients who remained FI at 12, 24, and 36 weeks in the two groups is shown in the graph in [Figure 3]b. Mean values of KPS score were also calculated for the two groups at 12, 24, and 36 weeks and was seen to fall from 73% to 75% at the beginning of the study to 60% at 36 weeks.

Normal neurocognitve function

The median period of NNF at 36 weeks for all patients in the study was calculated as 12 weeks. On comparison of the two groups by Kaplan–Meier method and Log-Rank test, we see that the period for Group 1 is 12 weeks (3 months) compared to 24 weeks (6 months) in Group 2 [Table 4] and [Figure 2]c. This difference of 12 weeks (3 months) was not found to be statistically significant (P = 0.312). The percentage of patients in the two groups that retained NNF at 12, 24, and 36 weeks is given in [Figure 3]c. Mean HMSE score was seen to fall from around 28 at the beginning of the study to 25 in Group 1, but remained around 28 in Group 2 at 36 weeks.

Cause of death due to neurological progression

About 44.4% (4 of 9) of patients who died in Group 1, died of progression of cranial or neurological disease, whereas only 12.5% (1 out of 8) of patients who died in Group 2, died of neurological or cranial causes [Table 4]. This difference is statistically not significant but is suggestive of a trend of better local control in patients receiving both modalities of treatment.

Effect of prognostic factors

The impact of prognostic factors such as RPA Class (1 or 2), number of brain metastases (single or multiple) and site of primary cancer (lung or breast) on survival was also evaluated by cross referencing them with survival rates in the two groups, but they were not found to have a statistically significant effect.

Discussion

Historically, WBRT is the standard of care for patients with multiple brain metastases. Addition of focal therapy has suggested the benefit of survival and local control in a subgroup of patients, though this is certainly not a universally applicable treatment for the heterogeneous group that constitutes patients of brain metastases. The study aims to find the subgroup of patients with single or multiple brain metastases (1–3) who may benefit from the addition of SRS to WBRT. The benefit we aim to measure is not only in terms of improvement of survival but also in the preservation of patients' FI and NNF.

The patients that were selected for this study were of minimum KPS of 70% and RPA class 1 or 2 only. The reasoning behind these inclusion criteria was to compare patients of good performance status, who are known from literature to have better survival, and see if the addition of focal therapy, in the form of SRS, to their treatment affects survival, period of FI and local control. We also kept selection criteria for only patients with NNF (defined by HMSE score) to be selected for the study. The idea again was to see if focal therapy (SRS) was able to prolong the period of NNF when compared with WBRT alone or if there was any negative effect of the added radiation dose to the brain on the neurocognitive function.

Survival

Median survival in the study group was recorded as 26 weeks or 6.5 months. This corresponds to the RTOG RPA classification^[24] where the expected median survival for patients with RPA class 1–2 is 4.2–7.1 months, respectively.

On comparing median survival in the two groups, we see that survival was 22 weeks for Group 1 and 27 weeks for Group 2. Thus, survival was higher by 5 weeks or 1.25 months in the group which added SRS to WBRT. This difference was not found to be statistically significant which maybe because of the small sample size of the study. However, this difference certainly shows a trend for improved survival in carefully selected patients even with multiple metastases (2–3). Comparing with the four major trials^{[17],[25],[26],[27]} of WBRT + SRS, in the setting of multiple brain metastases we see that survival results in the WBRT and WBRT + SRS groups correspond well with survival times seen in these studies [Table 5].

Table 5: Comparison of survival in our study with published literature

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Mean survival, though also calculated, was not compared for the two groups. This was because of the small sample size; the statistical tests for comparison would not be applicable. However, on a crude comparison, we see that again in the SRS boost group, the mean survival was higher by about 2.2 weeks than the WBRT group.

Another way that comparison of survival was made was by calculating, the percentage of patients surviving in both groups at every three monthly follow-up. At 3 months, the percentage was nearly equal, in fact slightly higher in the WBRT alone group, but as the study progressed, we see that a greater percentage of patients remained alive in the WBRT + SRS group. It was seen that more patients had died in the WBRT alone group than the WBRT + SRS group at the end of 9 months (8 out of 10 vs. 7 out of 11).

No separate subgroup analysis for patients with single metastases was performed in our study, but the majority of our patients (77%) had multiple brain metastases and hence, the results likely represent the cohort of 1–3 brain metastases.

The longest survival that was seen till the completion of our study was of a female with breast cancer, with a single brain metastasis in the cerebellum, controlled extracranial disease, and RPA class 1. She was from the WBRT alone group and survived for 60 weeks before succumbing to metastatic disease elsewhere in the body. The longest survival recorded in the SRS boost group was 44 weeks though the patient was still alive till the completion of our study.

Effect of prognostic factors

The three patient parameters, namely primary disease (breast vs. lung), number of brain metastases (single vs. multiple) and RPA class (1 vs. 2) are known from literature to have prognostic significance toward survival of the patient. In our study, no statistically significant correlation was found between these variables and overall survival likely because of the small sample size.

Effect on local control

We also compared the cause of death defined as cranial or extra-cranial in the two groups as a surrogate for local control of brain disease. About 44.4% of patients in the WBRT alone group died of the progression of neurological disease compared with only 12.5% in the WBRT + SRS group. We know from literature that about 50% of patients receiving WBRT alone progress in the brain as the biologically effective dose is subtherapeutic for solid tumors. This corresponds well with 44% cranial deaths in the WBRT alone group at 9 months. Interestingly, only 12.5% of patients in the WBRT + SRS group died of cranial causes at 36 weeks. This difference was not significant statistically, but it definitely suggests possible benefit of local control of brain metastases in favor of SRS boost.

In the RTOG 9508 trial^[17] local control was shown to be better with the SRS boost, but this had not translated into a lower death rate from neurological progression. As our study did not include repeat brain imaging during follow-up post treatment, as part of the protocol, a confident assessment of local control was hard to make but reduced death rate due to neurological cause should logically imply better control of the disease in the brain.

Functional independence

Performance status is also related to quality of life of the patient. Hence, we also attempted to compare whether there was any difference in the duration of good performance status of the patients in the two groups as it should be the attempt of every physician to provide not only a longer life to a patient with metastatic cancer but also a life of good quality for as much of his/her remaining days as possible.

The median period of FI was 12 weeks for Group 1 and 24 weeks for the WBRT + SRS group. This difference of 12 weeks or 3 months was not statistically significant, but it was seen that the period of FI nearly doubles in the SRS boost group compared to the WBRT alone group.

Brain metastases are a major cause of mortality as well as neurological morbidity which will directly affect the performance status of the patient. Controlling progression of these brain metastases by using WBRT leads to improved performance status as well as increased survival. In case of disease progression in the brain, both survival, as well as performance status, is affected. Thus, improved control of the metastases by adding SRS boost to WBRT, would probably be a reason for longer survival from neurological death and also a longer duration of FI in these patients compared to patients in the WBRT alone group.

The RTOG 9508 study^[17] reported that the performance measures were higher in the SRS boost group compared to the WBRT alone group. In the Cochrane database systematic review published in 2010 by Patil et al.,^[27] there was an improvement or stable KPS score at 6 months in 43% of patients in the WBRT + SRS group versus only 28% in the WBRT alone group (P = 0.03). A study by G. Minniti et al.^[28] reported that the follow-up changes in KPS due to neurologic deterioration were observed in 17 (26%) patients treated with WBRT plus SRS and in 30 (45%) patients treated with WBRT alone (P = 0.01).

Our results, though not statistically significant, similarly suggest improved performance status and period of FI in the WBRT + SRS boost group compared to the WBRT alone group.

Normal neurocognitive function

About 20%–65% patients of brain metastases have impaired neurocognition at presentation as per literature.^[29] Our attempt was to select patients who had maintained good neurocognitive function, and to see if by improving control of brain metastases we can improve on the preservation of neurocognitive function and hence, quality of life of patient.

The median period of NNF in the study group was 12 weeks. Patients in Group 1 had a median NNF of 12 weeks compared to 24 weeks in Group 2. This difference of 12 weeks or 3 months was not statistically significant, but there was a definite trend toward greater duration of NNF in the WBRS + SRS group. It is postulated that better local control of the brain metastases in the SRS boost group may have been the reason for a longer duration of NNF.

In a neurocognitive analysis of RTOG 91-04, Regine et al.^[30] demonstrated that approximately one-third of patients treated with WBRT experienced improvement in the mini mental state examination (MMSE); most importantly, those who had uncontrolled brain metastases had an average decrement of 6 points on the MMSE. In our study, the decrement in an average HMSE score was <3 points in the surviving patients in both groups, thus showing that patients, in whom disease was controlled by treatment were also able to enjoy a NNF.

Li et al.^[31] have also found that WBRT-induced tumor shrinkage correlated with better survival and neurocognitive function preservation. NCF was found to be stable or improved in long-term survivors, and tumor progression adversely affected NCF more than WBRT dose. In our study, 100% of the surviving patients in the SRS boost group at every 12 weekly follow-up maintained NNF. In the WBRT alone group, there was a percentage of surviving patients who developed cognitive dysfunction. The difference between these two fractions could not be compared in a statistically significant manner, but it appears that patients from the SRS boost group may have had better local control of brain metastases than the WBRT alone group and hence a greater possibility of maintaining NNF.

RTOG 9508 has shown that the addition of SRS to WBRT improved the FI of patients with brain metastases though there was no change in the mental status.^[17] In our study as well, surviving patients were able to maintain their NNF, with a fall of <3 in the average HMSE score in both groups.

Since the neurocognitive function of patients in the WBRT + SRS remained normal for a longer period, hence, there was also no evidence of increased neurotoxicity in the SRS boost group compared to the WBRT alone group.

Limitations of the study

The small sample size of our study could be the probable reason why the differences in survival in the two groups did not achieve statistical significance. None of the identified prognostic factors showed any co-relation with survival in our study. This may again be a result of the small sample size
Questionnaire-based evaluation of neurocognitive status such as MMSE and HMSE have been found to over-estimate neurocognitive impairment in patients over 60 years. These tests rely heavily on verbal response, reading, and writing and are difficult to interpret in a nonEnglish speaking population. We, however, tried to overcome this limitation with the use of HMSE which is better suited to the largely rural, Hindi speaking Indian population
Posttreatment imaging was not part of our follow-up protocol and hence, it is not possible to positively assess response to treatment and local control of disease
Only lesions amenable to SRS by Gamma-Knife Surgery were included in our study. There may be patients with multiple brain metastases in whom GKS may not be possible due to technical reasons such as size or location. Any recommendations made by this study would not apply to such patients
Neurocognitive side effects of WBRT usually start to appear at 9 months. However, follow-up of our study was limited to 9 months, and hence, it is possible that this treatment-related morbidity may have been missed.

Summary and Conclusions

The combination of WBRT and SRS showed a trend toward improved survival and local control in patients with 1–3 brain metastases. The addition of SRS to WBRT was also associated with a trend toward better preservation of performance status, neurological function and decrease in death due to neurologic causes, with no other significant toxicity
Longer survival, better preservation of performance status, and neurocognitive function and decreased risk of neurologic death in the WBRT + SRS group can be explained by better brain disease control compared to WBRT alone group
Results of this study may not have been statistically significant as the sample size of our study was small, and hence, they should not be over interpreted. Larger, adequately powered studies are required to identify the advantage of using SRS as a boost to WBRT in multiple brain metastases.

Acknowledgments

The authors would like to thank the Department of Radiology and Department of Neurosurgery, Army Hospital (R and R), New Delhi, India.

This study was financially supported by the Department of Radiology and Department of Neurosurgery, Army Hospital (R and R), New Delhi, India.

Financial support and sponsorship

This study was financially supported by the Department of Radiology and Department of Neurosurgery, Army Hospital (R and R), New Delhi, India.

Conflicts of interest

There are no conflicts of interest.

References

1.	Mehta M, Vogelbaum MA, Chang S, Patel N. Neoplasms of the central nervous system. In: De Vita VT Jr., Lawrence TS, Rosenberg SA, editors. Cancer: Principles and Practice of Oncology. 9^th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2011. p. 1700-49.
2.	Schellinger PD, Meinck HM, Thron A. Diagnostic accuracy of MRI compared to CCT in patients with brain metastases. J Neurooncol 1999;44:275-81.
3.	Bendell JC, Domchek SM, Burstein HJ, Harris L, Younger J, Kuter I, et al. Central nervous system metastases in women who receive trastuzumab-based therapy for metastatic breast carcinoma. Cancer 2003;97:2972-7.
4.	Davis PC, Hudgins PA, Peterman SB, Hoffman JC Jr. Diagnosis of cerebral metastases: Double-dose delayed CT vs. contrast-enhanced MR imaging. AJNR Am J Neuroradiol 1991;12:293-300.
5.	Gaspar L, Scott C, Rotman M, Asbell S, Phillips T, Wasserman T, et al. Recursive partitioning analysis (RPA) of prognostic factors in three radiation therapy oncology group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 1997;37:745-51.
6.	Lagerwaard FJ, Levendag PC, Nowak PJ, Eijkenboom WM, Hanssens PE, Schmitz PI. Identification of prognostic factors in patients with brain metastases: A review of 1292 patients. Int J Radiat Oncol Biol Phys 1999;43:795-803.
7.	Nieder C, Berberich W, Schnabel K. Tumor-related prognostic factors for remission of brain metastases after radiotherapy. Int J Radiat Oncol Biol Phys 1997;39:25-30.
8.	Swift PS, Phillips T, Martz K, Wara W, Mohiuddin M, Chang CH, et al. CT characteristics of patients with brain metastases treated in RTOG study 79-16. Int J Radiat Oncol Biol Phys 1993;25:209-14.
9.	Lutterbach J, Bartelt S, Ostertag C. Long-term survival in patients with brain metastases. J Cancer Res Clin Oncol 2002;128:417-25.
10.	Sperduto PW, Chao ST, Sneed PK, Luo X, Suh J, Roberge D, et al. Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: A multi-institutional analysis of 4,259 patients. Int J Radiat Oncol Biol Phys 2010;77:655-61.
11.	Borgelt B, Gelber R, Larson M, Hendrickson F, Griffin T, Roth R, et al. Ultra-rapid high dose irradiation schedules for the palliation of brain metastases: Final results of the first two studies by the Radiation Therapy Oncology group. Int J Radiat Oncol Biol Phys 1981;7:1633-8.
12.	Mintz AH, Kestle J, Rathbone MP, Gaspar L, Hugenholtz H, Fisher B, et al. A randomized trial to assess the efficacy of surgery in addition to radiotherapy in patients with a single cerebral metastasis. Cancer 1996;78:1470-6.
13.	Noordijk EM, Vecht CJ, Haaxma-Reiche H, Padberg GW, Voormolen JH, Hoekstra FH, 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;29:711-7.
14.	Patchell RA, Tibbs PA, Walsh JW, Dempsey RJ, Maruyama Y, Kryscio RJ, et al. A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 1990;322:494-500.
15.	Young K, Patchell RA, Regine WF. Palliation of brain and spinal cord metastases. In: Perez and Brady's Principles and Practice of Radiation Oncology. 5^th ed. Philadelphia, PA: Copyright, Lippincott Williams and Wilkins; 2008. p. 1974-85.
16.	DeAngelis LM, Delattre JY, Posner JB. Radiation-induced dementia in patients cured of brain metastases. Neurology 1989;39:789-96.
17.	Andrews DW, Scott CB, Sperduto PW, Flanders AE, Gaspar LE, Schell MC, et al. Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: Phase III results of the RTOG 9508 randomised trial. Lancet 2004;363:1665-72.
18.	Kaal EC, Niël CG, Vecht CJ. Therapeutic management of brain metastasis. Lancet Neurol 2005;4:289-98.
19.	Lippitz BE. Treatment of brain metastases using gamma knife radiosurgery – The gold standard. Euro Neurol Rev 2008;81-3.
20.	DeAngelis LM, Mandell LR, Thaler HT, Kimmel DW, Galicich JH, Fuks Z, et al. The role of postoperative radiotherapy after resection of single brain metastases. Neurosurgery 1989;24:798-805.
21.	Klein M, Heimans JJ, Aaronson NK, van der Ploeg HM, Grit J, Muller M, et al. Effect of radiotherapy and other treatment-related factors on mid-term to long-term cognitive sequelae in low-grade gliomas: A comparative study. Lancet 2002;360:1361-8.
22.	Taylor BV, Buckner JC, Cascino TL, O'Fallon JR, Schaefer PL, Dinapoli RP, et al. Effects of radiation and chemotherapy on cognitive function in patients with high-grade glioma. J Clin Oncol 1998;16:2195-201.
23.	Ganguly M, Ratcliff G, Chandra V, Sharma S, Gilby J, Pandav R, et al. A Hindi version of the MMSE: The development of a cognitive screening instrument for a largely illiterate rural elderly population in India. Int J Geriatr Psychiatry 1995;10:367-77.
24.	Gaspar LE, Scott C, Murray K, Curran W. Validation of the RTOG recursive partitioning analysis (RPA) classification for brain metastases. Int J Radiat Oncol Biol Phys 2000;47:1001-6.
25.	Kondziolka D, Patel A, Lunsford LD, Kassam A, Flickinger JC. Stereotactic radiosurgery plus whole brain radiotherapy versus radiotherapy alone for patients with multiple brain metastases. Int J Radiat Oncol Biol Phys 1999;45:427-34.
26.	Chougule PB, Burton-Williams M, Saris S, Zheng Z, Ponte B, Noren G, et al. Randomized treatment of brain metastases with gamma knife radiosurgery, whole brain radiotherapy or both. Int J Radiat Oncol Biol Phys 2000;48:114.
27.	Patil CG, Pricola K, Sarmiento JM, Garg SK, Bryant A, Black KL. Whole brain radiation therapy (WBRT) alone versus WBRT and radiosurgery for the treatment of brain metastases. Cochrane Database Syst Rev 2012;9:CD006121.
28.	Minniti G, Salvati M, Muni R, Lanzetta G, Osti MF, Clarke E, et al. Stereotactic radiosurgery plus whole-brain radiotherapy for treatment of multiple metastases from non-small cell lung cancer. Anticancer Res 2010;30:3055-61.
29.	Meyers CA, Smith JA, Bezjak A, Mehta MP, Liebmann J, Illidge T, et al. Neurocognitive function and progression in patients with brain metastases treated with whole-brain radiation and motexafin gadolinium: Results of a randomized phase III trial. J Clin Oncol 2004;22:157-65.
30.	Regine WF, Scott C, Murray K, Curran W. Neurocognitive outcome in brain metastases patients treated with accelerated-fractionation vs. accelerated-hyperfractionated radiotherapy: An analysis from Radiation Therapy Oncology group study 91-04. Int J Radiat Oncol Biol Phys 2001;51:711-7.
31.	Li J, Bentzen SM, Li J, Renschler M, Mehta MP. Relationship between neurocognitive function and quality of life after whole-brain radiotherapy in patients with brain metastasis. Int J Radiat Oncol Biol Phys 2008;71:64-70.