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Original Article
2022
:13;
219
doi:
10.25259/SNI_103_2022

Prognostic factors following resection of intracranial metastases

Corresponding author: Duncan Henderson, Department of Neurosurgery, Hull Royal Infirmary, Yorkshire, United Kingdom. duncanhenderson90@gmail.com
Licence

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, transform, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

How to cite this article: Henderson D, Zafar A, Bjornson A, Razak A, Achawal S, Danciut M, et al. Prognostic factors following resection of intracranial metastases. Surg Neurol Int 2022;13:219.

Abstract

Background:

The aim of this study was to identify prognostic factors associated with resection of intracranial metastases.

Methods:

A retrospective case series including patients who underwent resection of cranial metastases from March 2014 to April 2021 at a single center. This identified 112 patients who underwent 124 resections. The median age was 65 years old (24–84) and the most frequent primary cancers were nonsmall cell lung cancer (56%), breast adenocarcinoma (13%), melanoma (6%), and colorectal adenocarcinoma (6%). Postoperative MRI with contrast was performed within 48 hours in 56% of patients and radiation treatment was administered in 41%. GraphPad Prism 9.2.0 was used for the survival analysis.

Results:

At the time of data collection, 23% were still alive with a median follow-up of 1070 days (68–2484). The 30- and 90-day, and 1- and 5-year overall survival rates were 93%, 83%, 35%, and 17%, respectively. The most common causes of death within 90 days were as follows: unknown (32%), systemic or intracranial disease progression (26%), and pneumonia (21%). Age and extent of neurosurgical resection were associated with overall survival (P < 0.05). Patients aged >70 had a median survival of 5.4 months compared with 9.7, 11.4, and 11.4 for patients <50, 50–59, and 60–69, respectively. Gross-total resection achieved an overall survival of 11.8 months whereas sub-total, debulking, and unclear extent of resection led to a median survival of 5.7, 7.0, and 9.0 months, respectively.

Conclusion:

Age and extent of resection are potential predictors of long-term survival.

Keywords

Brain metastasis
Breast cancer
Nonsmall cell lung cancer
Stereotactic radiosurgery
Whole-brain radiotherapy

INTRODUCTION

The incidence of brain metastases is increasing, likely due to the improved systemic therapies resulting in prolonged overall survival[31,39] and improved radiological techniques, leading to increased diagnosis.[4,5,8,9,31,37,43] On the other hand, improved medical therapies can potentially decrease the incidence of brain metastases.[19] The most common malignancy, leading to brain metastasis, is nonsmall cell lung cancer (NSCLC),[4,5,9,11,28,37,45] followed by breast adenocarcinoma, melanoma, renal cell carcinoma, and colorectal adenocarcinoma.[4,5,8,9,11,14,19,20,28,30-33,37,41,43,45]

Craniotomy and resection of a brain metastasis can prolong overall survival in select patients.[1,4,7,10,11,14,20,26-28,34,41,43,45] Neurosurgeons may also resect metastatic lesions located intraventricularly, those which are durally based, within the pituitary gland and intraosseous within cranial bone. Ideal candidates for surgery include patients with a good performance status diagnosed with a solitary metastasis in a noneloquent area, associated with stable systemic disease.[4,11,27,28,45] Additional advantages of surgical resection include instant relief from symptoms of raised intracranial pressure due to mass effect, treatment of obstructive hydrocephalus without the need for cerebrospinal fluid diversion,[4,26,36,45] to provide histological diagnosis, reduce the need for Dexamethasone, improve functional performance status,[28,35] and facilitate stereotactic radiosurgery (STRS).[35] Surgical resection may not be required in patients with a metastasis <3 cm in maximal diameter, as these lesions can successfully be treated through STRS.[2,21]

MATERIALS AND METHODS

The aim of this study was to identify prognostic factors associated with resection of intracranial metastases. Before data collection, this study was formally registered with the local audit department, the ethics and methodology of the study were reviewed and signed off by the clinical governance lead. A retrospective study was carried out at a single center, Hull Royal Infirmary. Data collection occurred from May 12, 2021, to July 19, 2021. All patients who underwent attempted neurosurgical resection of a cranial metastasis between March 2014 and April 2021 were included in the study. Clinic letters, radiology and histology reports, and operation notes were used for data collection. One hundred and twenty-six patients were identified. However, 14 patients were excluded from the study and the reasons included; no available information, nonmetastatic histological diagnosis such as glioblastoma or lymphoma, biopsy of metastasis, treated through cyst aspiration, and insertion of Ommaya reservoir. Therefore, 112 patients were included who underwent a total of 124 resections. The diagnosis was concluded from the neurosurgical histological result and imaging available to the neuro-oncology multidisciplinary team. Biopsy results for any systemic lesions targeted were not available for analysis as these procedures would have been performed at a different hospital.

Neurosurgery clinic letters describing referral for consideration of whole-brain radiotherapy (WBRT) or STRS were not adequate to be recorded as having received treatment. The treatment reports stating the radiation dose (Gy) and fractions (WBRT) or number of target lesions (STRS) were reviewed to confirm adjuvant radiation administered. The extent of surgical resection was defined as unclear in patients where MRI was contraindicated, if they were too unwell for appropriate investigations, if no MRI was available, or if unable to distinguish residual from recurrent disease. Gross-total resection included cases where a postcontrast MRI did not demonstrate any residual enhancing material whereas cases were classified as sub-total resection if there was a tiny or small volume of enhancing material at the surgical site. Debulking included cases where there was either a large residual or limited resection performed. The extent of surgical resection was formally reported by a neuroradiologist and reviewed by a neurosurgeon.

Statistical analysis was carried out using GraphPad Prism 9.2.0 and P < 0.05 was deemed statistically significant. For the survival analysis, 1 month was defined as 28 days. Kaplan– Meier graphs were used and the statistical significance was calculated through the Log rank (Mantel–Cox) test.

RESULTS

The median age was 65 years old (24 to 84). The male-to-female ratio was 1:1.54 with 44 (39%) males and 68 (61%) females. There were 81 patients (72%) with a solitary cranial metastasis, 29 (26%) with multiple intracranial metastases, and in 2 (2%), MRI was contraindicated with only a preoperative CT available. The metastasis location most frequently involved the frontal lobe (frontal, frontoparietal, and frontotemporal [53 patients, 47%]), [Table 1]. Ninety-five (85%) were supratentorial intraparenchymal metastases, 5 (6%) were dural based, 2 (2%) were intraventricular, and 1 (1%) was within the pituitary gland. The most common presenting symptoms before dexamethasone treatment included: headaches (32%), motor deficit (31%), speech disturbance (31%), visual deterioration (15%), and seizures (13%), [Table 2].

Table 1:: Location of the primary neurosurgical target.
Table 2:: Preoperative clinical presentation.

The primary histological diagnosis was NSCLC in 63 patients (56%) which included one patient with an adenocarcinoma metastasis within a gliosarcoma, breast adenocarcinoma in 14 (12%), melanoma in 7 (6%), colorectal adenocarcinoma in 7 (6%), renal cell carcinoma in 6 (5%), esophageal adenocarcinoma in 4 (4%), endometrial sarcoma in 2 (2%), endometrial adenocarcinoma in 1 (1%), ovarian adenocarcinoma in 2 (2%), bladder transitional cell carcinoma in 1 (1%), anal squamous cell carcinoma in 1 (1%), prostate adenocarcinoma in 1 (1%), ethmoid air sinus adenocarcinoma in 1 (1%), and small cell lung cancer in 2 (2%).

Postoperative MRI with contrast was carried out within 48 hours of surgery in 63 patients (56%), between 3 and 7 days in 6 (5%) and was delayed or not performed at all in 41 patients (37%). MRI scanning was contraindicated in 2 patients (2%). Gross-total resection was achieved in 46 patients (41%), sub-total in 26 (23%), debulking in 9 (8%), and the extent of surgical resection was unclear in 31 patients (28%). Adjuvant STRS to the resection cavity was not carried out. However, 46 (41%) underwent radiation treatment for residual, recurrent, or additional intracranial metastatic disease. This included 27 (24%) who received WBRT, 18 (16%) received STRS, and 1 (1%) who received both WBRT and STRS [Supplementary Figure 1].

Of the total 112 patients, 10 (9%) underwent further resections of brain metastases, including 10 redo resections for recurrence at the surgical site and two resections of discrete lesions at a different intracranial site [Table 3]. Of the 124 tumor resections, 9 (7%) returned to theater for emergency neurosurgical intervention which included evacuation of intracranial hematoma (3, 2%), washout of brain abscess or subdural empyema (5, 4%), and decompressive craniectomy (1, 1%). There were 3 (2%) arterial territory cerebral infarcts and 4 (3%) new symptomatic venous thromboembolic events [Table 4]. The surgical mortality (death within 30 days due to an operative complication) was 1/124 (<1%).

Table 3:: Redo resection for recurrent intracranial metastatic disease.
Table 4:: Postoperative complications and return to theater.

At the time of data collection, 26/112 (23%) were still alive and the median follow-up for those patients was 1070 days (68– 2484). Including the total patient cohort, the rates of overall survival were as follows: 1 month = 93%, 6 months = 58%, 1 year = 35%, and 5 years = 17%, with a median survival of 233 days [Figure 1]. Of the 19 patients who died within 90 days of surgery, 5 (26%) had respiratory failure (causes included pneumonia, pulmonary embolism, and mediastinal lymphadenopathy), 5 (26%) had cancer progression (three had new systemic metastases and two had new intracranial metastases), and 6 (32%) had an unknown cause of death [Table 5].

Figure 1:: Kaplan–Meier graphs for survival analysis including all patients and then stratified by gender, age, and multiplicity of intracranial disease (median survivals and P values are displayed in Table 6).
Table 5:: Patients who died within 3 months of neurosurgical intervention.

Of the 10 patients who underwent redo resection and/ or resection of an additional cranial metastatic lesion [Table 3], 5 (50%) were alive at the time of data collection with a median follow-up of 1377 days (1099–2848). The median overall survival including all 10 patients was 1101 days (101–2848).

Age was significantly associated with survival (Log rank [Mantel–Cox] P = 0.009), with an age >70 being a negative prognostic predictor of survival [Table 6]. Extent of neurosurgical resection was significantly associated with survival (Log rank [Mantel–Cox] P = 0.022), with gross-total resection being a positive predictor of survival. Squamous subtyping of NSCLC was a negative predictor of survival (Log rank [Mantel–Cox] P = 0.048) [Figures 1 and 2]. On recursive partitioning analysis [Figure 3] using extent of resection and age, age <70 and confirmed gross-total resection yield a median survival of 27.5 months which was statistically significant (Log rank [Mantel–Cox] P = 0.0001).

Figure 2:: Kaplan–Meier graph for survival analysis stratified by histological diagnosis, adjuvant radiation treatment, and extent of neurosurgical resection (median survivals and P values are displayed in Table 6).
Figure 3:: Recursive partitioning analysis using age and extent of resection. GTR: Gross-total resection.
Table 6:: Survival analysis.

DISCUSSION

Our study demonstrated that achieving gross-total resection can lead to prolonged survival. However, there was a large number of patients (37%) where MRI scanning was either delayed or not performed at all, resulting in patients with an unclear extent of surgical resection. Neurosurgical services in England are commissioned by the National Health Service (NHS) based on guidelines written by the National Institute for Health and Care Excellence (NICE).[23] At present, NICE recommends MRI scanning within 72 hours of resection of malignant gliomas; however, this is not the case for brain metastases. It is common practice at Hull Royal Infirmary to perform an intraoperative ultrasound to evaluate the extent of resection; however, these results were not available for analysis. The long-term radiological follow-up was not assessed in our study. Our current protocol is MRI scanning every 3 months if residual disease is identified; however, once adjuvant STRS is completed the radiological follow-up is managed by the primary oncologist.

Schackert et al. found in their series of 127 patients; gross-total resection was associated with a longer duration of survival when compared to those with a residuum and median survivals of 10.6 and 5.8 months, respectively.[34] Olesrud et al. found in their study of 68 patients; no residual tumor, nonmeasurable residual tumor, and measurable residual tumor were associated with median survivals on 12.0, 9.5, and 5.6 months, respectively.[25] Sivasanker et al. found in their series of 124 patients; those who achieved gross-total resection had a median survival of 12.5 months and those who did not survived for a median of 4.2 months; however, this did not reach statistical significance.[38] Tendulkar et al. showed in their study of 271 patients; a median survival of 10.6 months following gross-total resection compared to 8.7 following subtotal resection; however, this did not reach statistical significance.[42] On the other hand, Jünger et al. found no difference in overall survival when comparing gross-total versus subtotal resection in 197 patients.[15]

Fluorescence-guided surgery using 5-aminolevulinic acid (5-ALA) has been shown to increase the likelihood of achieving gross-total resection in glioblastoma multiforme.[40] 5-ALA-guided resection of cerebral metastases has been attempted; however, the rate of tumor fluorescence is variable and its utility remains unclear.[12,16,17,44] Supramarginal resection can also be performed to reduce the probability of residual tumor; however, this is not common practice in the UK.[29] Intraoperative imaging modalities such as ultrasound can be used to facilitate gross-total resection.[6]

Our study demonstrates that redo resection can be safely performed in patients with recurrent intracranial metastases with good overall survival. However, earlier detection of recurrent disease and treatment with STRS could obviate the need for redo resection. 2/10 patients who underwent redo resection had an unknown extent of resection following their primary surgery. On the other hand, 4/10 of those who underwent redo resection had an MRI scan demonstrating gross-total resection following the primary surgery [Table 3]. Recurrence at the surgical site following gross-total resection could be due to new metastasis through disruption to the blood–brain barrier in the area, or it could be due to local residual tumor cells within the surrounding brain parenchyma which do not enhance during the contrast MRI. Yoo et al. demonstrated that extended microsurgical resection into the adjacent brain parenchyma of metastases located in noneloquent areas can significantly reduce the recurrence rate when compared to gross-total resection.[45] STRS to the resection cavity is routinely performed in some countries with the aim of reducing recurrent disease following gross-total resection;[3,15] however, this is not commissioned in the UK and STRS is mostly used for residual disease and concurrent metastatic lesions.[22]

Our study is limited by lacking postoperative Karnofsky performance status; this is likely a prognostic predictor of survival and can also affect a patient’s suitability for adjuvant radiation treatment. There was no patient reported quality of life assessment. Furthermore, we do not state the value in symptomatic relief provided by surgical resection, such as relieving headaches or improving neurological deficits secondary to mass effect and cerebral edema. We also do not present the details of systemic treatments such as chemotherapy, as this service is managed in a different hospital.

The dose and duration of dexamethasone administration are missing. Dexamethasone can provide symptomatic relief and reduce the risk of neurological deterioration while awaiting surgery. Hutchinson et al. showed in a randomized controlled clinical trial that dexamethasone was associated with a higher incidence of unfavorable outcome (moderately severe disability to dead) in patients with chronic subdural hematoma; in particular, dexamethasone was associated with a higher incidence of infection.[13] While these results may not be applicable to neuro-oncology patients; in our study, 4% died within 90 days of surgery due to pneumonia and 4% returned to theater due to surgical site infection.

Data on cigarette smoking were missing from our study. Concurrent cigarette smoking increases the risk of surgical site infection, pneumonia, and perioperative mortality.[18,24] Cigarette smoking can also cause other medical comorbidities such as chronic obstructive pulmonary disease which could contribute to poor clinical outcome. In our study, squamous NSCLC carried a shorter duration of survival than nonsquamous NSCLC (P = 0.048), this could potentially be explained by the greater association between cigarette smoking in squamous NSCLC than adenocarcinoma.

Death due to an unknown cause within 90 days of surgery occurred in 5% of the patients. These patients could have potentially died of a preventable cause such as surgical site infection, seizures, or venous thromboembolism. However, these patients may have chosen to not undergo further hospital admission, to focus on palliative symptomatic relief in their home. Furthermore, postmortem investigations are seldom performed in patients with metastatic cancer because it often does not add helpful information to the family members and can cause distress. While this is understandable, it is difficult to improve our service when there is missing information on the causes of postoperative death.

During the time period of data collection, there has been a change in the preferred adjuvant radiation treatment in our service. In 2017, Brown et al. demonstrated that when compared against WBRT, STRS is associated with a longer duration of cognitive-deterioration-free survival and no difference in overall survival for patients undergoing adjuvant radiation treatment to the surgical cavity following resection of a solitary brain metastasis.[3] Our study includes patients who underwent surgery between March 2014 and April 2021, and in the early years, WBRT was common practice; however, currently, STRS is most frequently used. As our study was retrospective, it did not include cognitive-deterioration-free survival as an outcome. A significant number of patients did not receive cranial radiation treatment and potential explanations for this include; the patient died before treatment was administered, patient choice, radiation treatment not offered in cases where a solitary metastasis had been completely resected as this is not recommended by NHS England, and logistical errors as the service transitioned from WBRT to STRS as these treatments are carried out by different clinical teams working in separate hospitals.

Given the impact of the COVID-19 pandemic on neurooncology services in the UK (37), this could have led to a reduction in overall survival for some patients in this study.

CONCLUSION

Cranial metastatic disease represents a heterogeneous patient population with multiple factors influencing the clinical outcome, therefore, when considering neurosurgical intervention, each case should be considered on an individual basis. There are ongoing advancements, with new medical therapies becoming available for different types of cancer in which neurosurgeons may not be aware of. Therefore, input from oncologists who treat the primary disease is crucial when selecting patients who would be suitable candidates for neurosurgical intervention. Early postoperative MRI scanning is recommended to identify residual tumor or new discrete lesions which could benefit from adjuvant STRS. If required, redo resection can successfully be performed with benefits to overall survival. In our study, age and extent of surgical resection were prognostic predictors of survival.

Declaration of patient consent

Patient’s consent not required as patient’s identity is not disclosed or compromised.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

SUPPLEMENTARY FIGURE

Supplementary Figure 1:: Bar charts showing multiplicity of intracranial disease, day postoperative MRI performed and extent of resection and adjuvant radiation treatment.

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