Cerebellar Re-Irradiation after whole brain radiotherapy Significant Symptom Relief with Minimal Toxicity in Metastatic Brain Patients

doi:10.21203/rs.3.rs-4436485/v1

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Cerebellar Re-Irradiation after whole brain radiotherapy Significant Symptom Relief with Minimal Toxicity in Metastatic Brain Patients

https://doi.org/10.21203/rs.3.rs-4436485/v1

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Introduction

Whole-brain irradiation (WBRT) remains a standard treatment for patients with extensive brain metastases, providing symptom relief and prolonging survival. However, patients often experience recurrent metastases, necessitating re-irradiation. This study evaluates the efficacy and safety of cerebellar-only re-irradiation for improving symptoms and reducing toxicity in patients with recurrent cerebellar metastases following WBRT.

Methods

A retrospective review was conducted on patients who underwent cerebellar re-irradiation between 2017 and 2023 after prior WBRT for symptomatic cerebellar metastases. Clinical, dosimetric, and outcome data were collected. Symptom improvement was assessed based on patient, caregiver, and physician reports three months post-treatment.

Results

The study included 56 patients with a median age of 53 years. Symptom domains included gait dysfunction, nausea/vomiting, dysarthria, movement disorder, dizziness, and headache. Breast cancer was the most common histology. The median interval from WBRT to cerebellar re-irradiation was 15 months. Symptomatic improvement was observed in 75% of patients, with notable improvements in nausea/vomiting (84.6%) and headache (80%). Age, dose deliver and time from WBRT were significant for clinical improvement. Dexamethasone use decreased in 76.3% of patients post-treatment. Radiological responses correlated with clinical improvements in 90% of cases. Only one patient developed symptomatic radiation necrosis. Six-month overall survival and progression-free survival were 50% and 39.2%, respectively.

Conclusion

Cerebellar-only re-irradiation is an effective and safe option for managing recurrent cerebellar metastases, significantly improving symptoms with minimal toxicity. This approach also allows for subsequent systemic therapy or radiosurgery for supratentorial lesions, potentially reducing the need for additional WBRT. Further studies are required to validate these findings in larger cohorts.

Brain metastases

Radiotherapy

Cerebellum

Whole-brain irradiation (WBRT) remains a standard choice of treatment and is indicated for many patients with these tumors. {1}

Although hypofractionated stereotactic radiotherapies (SRTs) have become more common for treating patients with minimal brain metastases, some patients are not eligible to undergo SRT or surgery because of extensive brain metastases; instead, they receive whole-brain (WB) radiotherapy (WBRT) as first-line treatment. {2} For patients with extensive intra-cranial metastatic disease, WBRT provides symptom relief and prolongs survival. Several studies have also shown that cancer patients with brain metastases had an overall response rate of 75–85%, as estimated by symptom improvement or stabilization, and had an appreciable progression-free survival (PFS) period after receiving WBRT. {3}.

Unfortunately, for some patients, re-irradiation is needed due to progressive brain disease. For these patients, re-WBRT may improve symptoms due to brain metastasis recurrence.{4} Central nervous system toxicity is an essential concern for physicians when considering re-WBRT, especially in patients for whom cognitive decline is a significant concern. {5}

While most of these cancers metastasize to the supratentorial space, approximately 10–20% also metastasize to the posterior fossa.{6) Unlike most supratentorial counterparts, Cerebellar metastases can cause significant symptoms that are out of proportion with their size. These cerebellar lesions can cause obstructive hydrocephalus, brainstem compression, and herniation with acute neurological decline. This increased propensity for rapidly progressive symptoms makes these lesions appear clinically distinct from supratentorial lesions, with different presenting symptoms, risk profiles, treatment strategies, and potential outcomes.{7)

In addition to unique clinical presentation, Patients with significant cerebellar disease have poorer prognosis. {7.8}

Treating the cerebellum only in re-radiation may improve symptoms, control rapidly deteriorating disease, and decrease some side effects of re-WBRT. In addition, it may create an opportunity for response to systemic therapy or salvage radiosurgery for supra-tentorial lesions.

This study aimed to determine whether cerebellar-only brain re-irradiation with or without focal stereotactic radiosurgery for supra-tentorial lesions was beneficial by conducting a retrospective analysis of cases from our institution.

Following institutional review board approval (0265-23-SMC), a retrospective review of patients undergoing re-irradiation between 2017 and 2023 for symptomatic brain metastases in the cerebellum after whole-brain radiotherapy was conducted. Clinical, dosimetric, and outcome data were collected and analyzed. Symptom data was searched in the patients' files before and three months after cerebellar radiation. Improvement of de-conditioning was considered based on patients' reports, caregiver reports, or physician reports.

Statistical analyses were performed utilizing SPSS software (IBM, Chicago, USA version 29). All cases were discussed in a neuro-oncological tumor board meeting. In all cases, progressions of brain metastases were confirmed by MRI studies of the brain after the initial course of whole-brain irradiation.

In this cohort, we analyzed 56 patients who had re-irradiation to the cerebellum only after WBRT. The median age was 53 (28-68). The Karnofsky performance status ranges from 70-90. All patients had cerebellar symptoms, which we divided into six main domains: 1) Gait dysfunction, 2) nausea and vomiting, 3) Dysarthria, 4) movement disorder, 5) dizziness, and 6) headache.

In regards to histology, breast cancer was the most prevalent histology with 40 patients. The others were Small cell lung cancer (8), ovary adenocarcinoma (4), Non-small cell lung adenocarcinoma (3), and one Melanoma. The median time from WBRT to cerebellar RT was 15 months (8-25). The WBRT Technique was 3D in 85% and VMAT with hippocampal avoidance in 15%. 92% of patients received 30Gy in 10 fractions in the WBRT regiment, with the others 20Gy in 5 fractions. Figure 1,2,3.

Cerebellar RT was delivered using 3D and VMAT in 57.2% and 42.8% of the cohort. Most (75%) received systemic therapy during or pre/post-RT course. 46% received radiosurgery for supra tentorial lesion after cerebellar RT treatment. With a median of 5 lesions (1-11) and a median dose of 20 (16-24), all received single-fraction treatment.

The dose regiment was more heterogeneous: 20Gy in 10f (21.4%), 25Gy in 10f (21.4%), 25Gy in 5f (17.8%), 24Gy in 6f (17.8%), 30Gy in 12f (10.7%), and 30Gy in 10f (10.7%). Table 1 shows that the median follow-up time was 14 months (6-23).

Symptomatic therapy with Dexamethasone dosages between 2mg-16mg per day was given to 67.8% (38) of the cohort before the second RT course.

Clinical outcome

All patients were symptomatic, with most presenting with more than one domain of cerebellar syndrome. The neuro-oncologist examination reported symptomatic improvement in 75% (42), with a median time to improvement ranging from 2 to 8 months post-radiation. Among the other 25% (7 patients), 4 had stable neurological symptoms, and in the other 3, there was deterioration.

Among the 42 cases with symptomatic improvement, 38 had cerebellar metastasis disease only. Of the other 5 cases with supra-tentorial lesions, 4 had a significant burden with mass effect symptomatic motor weakness and aphasia. For them, radiosurgery was planned after cerebellar RT and was given successfully. One patient had only a minor disease, and the decision was made to treat only the cerebellum.

The most common clinical improvement was in nausea and vomiting, with 22 out of 26 (84.6%) patients reporting improvement. Gait dysfunction improved in 8 out of 20 (40%) patients. Dysarthria improved in 6 out of 14 patients (42%), movement disorder in 10 out of 18 patients (55%), dizziness in 14 out of 24 (58.3%), and headache in 12 out of 15 (80%) patients.

Dexamethasone use was decreased in 76.3% (29/38) of patients after RT treatment. In 89.8% (26/29), the reason was a symptomatic improvement.

In 90% of patients with improved neurological function or neurological stability, there was a radiological response using the Radiological response assessment method. In comparison, in all patients with clinical deterioration, there was a radiological progression.

Six months' overall survival from the start of re-radiation was 50%, with progression-free survival of 39.2%.

Factors related to clinical improvement after cerebellar re-irradiation is shown in Table 2. in univariable analysis The following were significant factors related to clinical improvement after re-irradiation: age (<40 with OR of 0.56 {CI95% 0.1-0.86}, p=0.023), time from 1st RT (>18 months with OR of 0.67 {CI95%0.42-0.86}, P=0.034) and dose Equivalent dose in 2 Gy fractions (EQD2)(>30Gy with OR of 0.67 {CI95% 0.24-0.91}, p=0.042 ).

Toxicity

Among the 56 patients who were treated for re-RT in the cerebellum, only 1 developed symptomatic radiation necrosis (RN). This patient was 44 years old with a diagnosis of breast cancer. She received 30Gy in 10 fraction WBRT using the 3d technique, and five months later, due to progressive, symptomatic disease at the cerebellum, she received the second course of 25Gy in 5 fraction. She presented with headache and vomiting five months after 2nd RT course. At the Follow-up MRI, she had significant edema with a decrease in the size of metastatic lesions. After multi-parametric MRI, including a TRAM sequence, RNs favored it in a tumor board discussion. She needed to increase the Dexamethasone dosage up to 16 mg twice daily. Three weeks after Dexamethasone treatment, she had relief in symptomatic burden. Unfortunately, due to progressive systemic disease, this patient died eight months after the 2nd RT course.

In this retrospective study, we aim to show that re-irradiation to the cerebellum is feasible and does have clinical benefits. Previous studies have shown that there have been a limited number of articles in the literature describing re-WBRT with acceptable toxicities, minimal side effects, and a treatment that provides symptomatic relief.{4.9} Over the years, radiation oncologists have become more generous when indicating a second course of WBRT, especially in patients where the time to prior WBRT is longer and extracranial disease remains controlled.

Overall symptomatic improvement after Re-WBRT is between 24–74% among different studies [4,9,10]. Measuring symptomatic improvement is problematic and can result from significant bias dependent on the measurement toll. In our study, the overall symptomatic rate was higher than previously reported, with a 75% improvement after three months. Clinical variables impact symptomatic improvement, including longer intervals between RT course, age, and performance status. Age and performance status are known factors that impact OS in patients with brain metastases and are part of the GPA assessment. Longer time between RT courses may imply less aggressive intrinsic biology of the underlying metastases, creating an opportunity for average brain recovery.{11}

In our study, symptoms of nausea, vomiting, and headache had the highest chance for improvement, with at least 80% improvement after RT. This may be because those symptoms relate to increasing ICP, perhaps due to pressure on the fourth ventricle. Decreasing the pressure by treating the underlying cause can result in a rapid and significant clinical response. Other symptomatic domains, including dizziness, gait ataxia, and movement disorder, are usually a result of intrinsic cerebellar injury, which is more difficult to recover from even after treatment. {12,13}.

In our study, the measurement of symptomatic improvement was analyzed retrospectively by looking into patients' files and physician-reported free text summaries. This method has a significant intrinsic bias{14}, explaining the high percentage of clinical improvement. Another measurement of cerebellum burden, including patients' reported outcome using the 70-item Patient-Reported Outcome Measure of Ataxia, was scored on a 0–4 Likert scale. While validated and consistent, this measurement is time-consuming and difficult for metastatic oncologic patients with low-performance status. {15,16}

The toxicity of re-irradiation is low, as previously published.{4.10} In our cohort, there was only one 1 case of symptomatic RN, which is 1.7% of the cohort. Several known factors impact RN incidence. Among them is the time between RT courses (higher incidence with interval < 6 months) and the cumulative BED (higher incidence with dose > 120Gy).{17} The fact that the patient in our cohort who developed RN had received a 2nd RT course less than six months and received a BED of 126.7Gy is consistent with previous knowledge.

Another Late radiation toxicity is cognitive decline.{18} Most data is related to WBRT. The hippocampi are a well-known organ that relates to radiation injury and subsequent cognitive decline with robust data on dose constraints and radiation planning to avoid high doses to this organ.{19) The cerebellum impacts cognitive decline after RT, with most pediatric posterior fossa RT data. This mechanism of cerebellar injury after RT may be different and longer than the hippocampi injury mechanism.{20} Because most oncology patients who received the 2nd RT course have a poor prognosis with a median OS of 4–5 months, the cognitive decline after Cerebellar 2nd RT may not be as significant.

Our study has several limitations, including retrospective analysis and measurement quality. Nonetheless, several strengths include a relatively large cohort of unique clinical approaches.

Despite the relative commonality of cerebellar metastases, studies on their clinical outcomes are limited. Most of these studies combine infratentorial and supratentorial lesions into the same study cohort, masking the outcomes for patients with less known cerebellar metastases.

Our case series presents the outcomes of patients treated with cerebellar-only re-irradiation. This approach results in a high percentage of clinical symptomatic improvement with little toxicity. Age, dose deliver and time from WBRT were significant for clinical improvement. In addition, several patients were able to receive radiosurgery to supra tentorial lesions instead of re-WBRT after cerebellar-only re-RT, which may decrease toxicity. This approach needs to be validated in more extensive trials.

Ethics approval and consent to participate-an IRB approval was given. 0265-23-SMC. in accordance with the Declaration of Helsinki

Availability of data and materials-All information and data material are available.

Funding-none.

Patients treated in this cohort have had informed consent to the use of radiation planning and medical chard for research properties

The experimental data and the simulation results that support the findings of this study are available

Author Contribution

OH -DATA analysis, statistical analysis, prepared figures and wrote main manuscrip MJ-english editing and scientific review YL-scintific review and radiation dataAT-scientific review and neurological data

Acknowledgement

i wish to acknowlegde the contibution of all neuro-oncological team at Sheba medical center

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Table 1 Patients characteristics

n	56
Age (mean, range)	53 (28-68)
Histology Breast CA ER/PR +, Her-2 neg Breast CA HER-2 Positive Breast CA triple negative Small cell lung CA Ovary CA Non-small cell lung CA Melanoma	20 13 7 8 4 3 1
Median time from 1 RT	15 Month (8-25)
1^st RT dose (WBRT) 30GY in 10 fraction 20Gy in 5 fraction	92% 8%
KPS in 2 RT	80 (70-90)
Symptoms* Nausea Gait dysfunction and imbalance Dysarthria Movement disorder Dizziness Headache	46% 35.7% 25% 32.1% 42.8% 26.7%
Symptomatic improvement at 3 month	75%

*Total doesn't reach 100% with most patients presented with more than one symptom. CA-cancer, RT-radiotherapy, WBRT-whole brain radiation therapy, KPS-karnofsly performance status.

Table 2 variables impact clinical improvement

variable	OR (CI95%), P
Age <40y	0.56(0.1-0.86), 0.023
EQD2>30Gy	0.67 (0.24-0.91),0.042
Histology breast Ca	0.84 (0.3-1.5), 0.091
Time from WBRT>18months	0.67 (0.42-0.86), 0.034
KPS>70	0.79 (0.057-2.2), 0.12

EQD2-equivalent dose at 2 Gy fractions, CA-cancer, WBRT-whole brain radiation therapy, KPS-karnofsly performance status.

No competing interests reported.

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Cerebellar Re-Irradiation after whole brain radiotherapy Significant Symptom Relief with Minimal Toxicity in Metastatic Brain Patients

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Abstract

Figures

Introduction

Methods

Results

Discussion

Conclusion

Declarations

Author Contribution

Acknowledgement

References

Tables

Additional Declarations

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