Impact of Short Versus Long Course Whole Brain Radiation Therapy on Memory Function in Brain Metastasis Patients

AUTHORS

Sridhar Poojar 1 , Rahul Loni 1 , * , Krishna Raj H K 1 , Thimmaiah Naveen 1 , V Lokesh 1

1 Kidwai Memorial Institute of Oncology, Bangalore, India

How to Cite: Poojar S, Loni R, H K K R , Naveen T, Lokesh V. Impact of Short Versus Long Course Whole Brain Radiation Therapy on Memory Function in Brain Metastasis Patients, Rep Radiother Oncol. Online ahead of Print ; 6(1):e95524. doi: 10.5812/rro.95524.

ARTICLE INFORMATION

Reports of Radiotherapy and Oncology: 6 (1); e95524
Published Online: October 12, 2019
Article Type: Research Article
Received: June 19, 2019
Revised: August 27, 2019
Accepted: September 23, 2019
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Abstract

Background: Most common intracranial tumor in adults is brain metastasis. Different fractionation schedules used for whole brain radiation therapy are 20 gray/5 Fr, 30 gray/10 Fr, and 40 gray/20 Fr, which in four weeks have shown equivalent response rate, period of improvement, palliative effect, time to disease progression, and survival. However, there is lacking literature on the effect of different fractionation schedules of radiation therapy on memory function.

Objectives: Hence, we evaluated memory function in two different fractionation schedules of whole brain radiation therapy (WBRT) in patients with brain metastases.

Methods: A total of 20 patients, who were histologically proven primary and recently diagnosed brain metastases, with a RPA class of I/II, and satisfying eligibility criteria were taken into this study. Patients were randomly assigned to whole brain radiation therapy of 40 gray in 20 fractions (group A) and 30 gray in 10 fractions (group B) with concurrent Temozolomide. Memory function assessment was done using P.G.I. Memory scale before, during, and after the treatment, as well as at three months and six months of follow-up. Two groups were compared for with appropriate statistical tests.

Results: Patients in group A showed improvement in five domains of memory function (attention and concentration, remote and recent memory, mental balance and verbal retention for similar pair) during radiation therapy, compared to group B patients. However, deterioration of memory function was noted in both groups at 3- and 6-months post chemoradiation therapy.

Conclusions: Fourty Gy in 20 fractions given over four weeks with concurrent TMZ 75 mg/m2 is a better and preferable treatment option for patients with brain metastasis with respect to memory function.

Keywords

Whole Brain Radiotherapy (WBR) Brain Metastases Memory Function

Copyright © 2019, Reports of Radiotherapy and Oncology. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited.

1. Background

Metastasis to the brain is one of the most common intracranial tumors in adults. An important cause of morbidity and mortality in 10% to 30% of adult cancer patients is brain metastasis (BM) (1). As per the American Cancer Society, in the United States, each year 170000 cancer patients develop brain metastasis, with most of them having two or more metastases (2). Lung cancer is the most common primary cause of brain metastases and is accountable for nearly half of all secondary tumors of the brain. Other major primary tumors comprise of breast cancer, melanoma, and colorectal cancer.

Brain metastasis patients with different signs and symptoms range from an incidental imaging finding to changes in mental status, seizures, headache, dizziness, blurred vision, nausea, weakness or aphasia. Symptoms usually progress over a period of a few weeks. However, with tumors like malignant melanoma, thyroid carcinoma, renal cell carcinoma, and choriocarcinoma, patients may present with hemorrhage into the metastases, which can cause a more dramatic presentation (3). Patients are managed with symptomatic care and definitive treatment. Multiple lesions or widespread metastatic disease is seen in the majority of patients at presentation. Whole brain radiotherapy (WBRT) is the standard treatment (4, 5). SRS have the advantage over resection. With respect to overall survival no statistically significant is noted with different fractionation schedules and doses. With respect to tolerability, short treatment time, cost-effectiveness, and trend for better survival 30 gray/10 fractions have become the standard of care (6). Systemic chemotherapy in brain metastases patients is rapidly growing as a treatment option. Antonadou et al., suggested that concomitant whole brain radiotherapy and temozolomide improves quality of life (7).

The effect of WBRT on neurocognitive dysfunction and dementia is poorly understood. A study conducted at Memorial Sloan Kettering Cancer Center demonstrated that patients surviving one year or more after WBRT had an 11% risk of dementia (8).

2. Objectives

However, there is no study clearly showing the decline in memory function in brain metastases patients undergoing WBRT treatment. Hence, in this study we are evaluating memory function outcomes in patients receiving WBRT with two different fractionation schedules with concurrent TMZ.

3. Methods

3.1. Eligibility Criteria

The Medical Ethics Review Board approval was sought for the study protocol and consent procedure. Patients aged 18 - 70 years with Karnofsky performance status (KPS) of more than or equal to 70, with a histologically proven systemic tumor, radiologically diagnosed brain metastases, and without a history of metastatectomy, radio-surgery, or chemotherapy in the previous three weeks and prior radiation to brain were eligible. Patient and tumor characteristics are as shown in Table 1.

Table 1. Patient and Tumor Characteristicsa
Group AGroup BP Value
Total10 (100)10 (100)
Age0.910
21 - 301 (10)1 (10)
31 - 402 (20)1 (10)
41 - 504 (40)4 (40)
51 - 602 (20)4 (40)
> 601 (10)0 (0)
Gender1.000
Male4 (40)3 (30)
Female6 (60)7 (70)
KPS1.000
702 (20)2 (20)
805 (50)5 (50)
903 (30)3 (30)
Neurological deficit0.160
Yes2 (20)5 (50)
No8 (80)5 (50)
Site of primary tumor1
Lung8 (80)7 (70)
Breast1 (10)0 (0)
Bronchogenic carcinoma1 (10)1 (10)
Choriocarcinoma0 (0)1 (10)
Metastasis of unknown origin0 (0)1 (10)
BSA0.532
< 1.30 (0)2 (20)
1.3 - 1.610 (100)7 (70)
> 1.60 (0)1 (20)
Number of brain metastases1.000
11 (10)1 (10)
2 - 48 (80)8 (80)
> 41 (10)1 (10)

Abbreviations: BSA, body surface area; KPS, Karnofsky performance status.

aValues are expressed as No. (%).

Informed consent was taken. Patients were randomly assigned into two groups; whole brain radiation therapy with 40 gray/20 fractions (group A) and 30 gray/10 fractions (group B). Concurrent chemotherapy was given in both groups.

3.2. Radiation Therapy

For WBRT, the entire brain parenchyma and meningeal reflections were treated.

3.3. Chemotherapy

Half an hour before radiation therapy, patients in both arms received capsule temozolomide (TMZ), 75 mg/m2, five days a week, orally, under fasting condition, along with prophylactic oral antiemetic (ondansetron 8 mg OD) before TMZ.

3.4. Memory Function Assessment

Memory function assessment was done using P.G.I. Memory scale before, during, and after the treatment, as well as at three months and 6 months of follow-up (Tables 2-8).

Table 2. Remote Memory (Maximum Score 6)
Remote Memory (Maximum Score 6)Group AGroup BP Value
Before RT5.40 ± 0.705.10 ± 0.320.232
During RT5.70 ± 0.485.10 ± 0.320.004**
After RT5.70 ± 0.485.00 ± 0.470.004**
3 months5.11 ± 0.934.43 ± 0.530.106
6 months5.00 ± 0.004.50 ± 0.710.667
Table 3. Recent Memory
Recent MemoryGroup A (Mean Rank)Group B (Mean Rank)P Value
Before RT11.89.20.353
During RT11.69.40.436
After RT14.86.20.001
3 months9.6110.350.78
6 months8.5611.30.315
Table 4. Attention and Concentration
Attention and ConcentrationGroup A (Mean Rank)Group B (Mean Rank)P Value
Before RT9.4511.550.436
During RT8130.063
After RT14.056.950.005
3 months8.2811.550.211
6 months9.0610.850.497
Table 5. Delayed Recall (Maximum Score 10)
Delayed Recall (Maximum Score 10)Group AGroup BP Value
Before RT7.90 ± 0.887.90 ± 0.881.000
During RT8.20 ± 0.928.00 ± 0.820.613
After RT8.00 ± 1.057.90 ± 0.990.830
3 months7.67 ± 1.227.86 ± 1.070.749
6 months7.00 ± 0.008.00 ± 1.410.667
Table 6. Immediate Recall (Maximum Score 12)
Immediate Recall (Maximum Score 12)Group AGroup BP Value
Before RT9.10 ± 1.528.80 ± 1.320.643
During RT9.80 ± 1.698.90 ± 1.370.207
After RT9.50 ± 1.728.70 ± 1.640.300
3 months8.44 ± 1.678.43 ± 1.620.985
6 months6.00 ± 0.009.50 ± 0.710.154
Table 7. Verbal Retention for Similar Pairs
Verbal Retension For Similar PairGroup A (Mean Rank)Group B (Mean Rank)P Value
Before RT11.459.550.481
During RT10.2510.750.853
After RT14.456.550.002
3 months8.7811.10.4
6 months9.2210.70.604
Table 8. Verbal Retention for Dissimilar Pairs (Maximum Score 15)
Verbal Retention for Dissimilar Pairs (Maximum Score 15)Group AGroup BP Value
Before RT10.40 ± 0.9710.70 ± 1.060.517
During RT10.70 ± 1.1610.70 ± 1.061.000
After RT10.70 ± 1.0610.10 ± 1.790.374
3 months8.89 ± 1.839.43 ± 0.790.481
6 months8.00 ± 0.0010.00 ± 0.00-

3.5. Follow-up

Patients were followed-up for a period of six months’ after chemo radiation therapy.

4. Results

4.1. Statistical Methods

Data analysis was done using the statistical software SAS 9.2, SPSS 15.0, Stata 10.1, MedCalc 9.0.1, Systat 12.0, and R environment Ver.2.11.1. A P value of less than 0.05 is taken as a significant relationship.

5. Discussion

An ability to retain and reproduce intentionally perceived impression is memory (9, 10). This definition includes compartmental views of very short term, short term, and long-term memory. Working memory is often used to denote short term memory. Short-term memory allows a recall for a period of several seconds to a minute without rehearsal. Its capacity is also very much limited. Long-term memory can store much larger quantities of information for potentially unlimited duration (sometimes a whole life span). Its capacity is immeasurable. Information is encoded acoustically in short term memory and semantically in long term memory. Transient patterns of neuronal communication support short-term memory and is dependent on regions of the frontal lobe and the parietal lobe. On the other hand, long-term memory is supported by permanent changes in neural connections. Short term memory is consolidated into long term memory in hippocampus.

Recent research in humans showed that DNA methylation, or prions, are responsible for long-term memory storage (11). In the recognition memory task it is evaluated whether an individual had an encounter with a stimulus like a picture or a word before.

Ecognition memory tasks require individuals to indicate whether they have encountered a stimulus (such as a picture or a word) before. In the recall memory tasks, participants are asked to retrieve previously learned information.

Neuro toxicity is noted in brain metastasis patients who have received WBRT, especially declarative memory. The study of Chang et al., observed a greater decline in memory [as demonstrated by the Hopkins verbal learning test revised (HVLT-R)] at four months, in the SRS plus WBRT group compared to SRS alone (12). This decline in memory has been described as part of a biphasic pattern of cognitive loss. Post WBRT initial deterioration was noted in multiple domains of cognitive function, which peaks around four months post radiation.

They study of DeAngelis et al. (8), on 12 patients treated with WBRT (25 - 39 Gy in three to six Gy per fractions), dementia, ataxia, and incontinence was noted in all the patients at a median of 14 months after WBRT. However, actual incidence of radiation induced dementia is much lower in modern practice as smaller fraction sizes are used.

Studies using these regimens in conjunction with neurocognitive follow-up have suggested general stability in neurocognitive function for most patients in the short to medium term after whole brain radiotherapy in the absence of tumor recurrence. In addition, in our study, we noted the improvement in four domains of memory function in patients treated with two Gy per fraction during radiation therapy.

However, decline in memory function was noted in both groups at three and six months post treatment assessment of memory function. The short-coming of our study is the small population of patients. Hence it needs to be confirmed in a study with a larger population. In addition, an improvement in the memory function might be due to the specific location in the brain, hence it also needs to be analyzed further.

5.1. Conclusions

Therefore, we conclude that 40 Gy in 20 fractions given over four weeks, with concurrent TMZ, is better and a preferable treatment option for patients with brain metastasis with respect to memory function. However, it needs to be confirmed in a study with a larger population.

Footnotes

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