Neurosurgery notes/Tumours/Metastatic CNS tumour/Brain mets Management

Brain mets Management

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Metastatic CNS tumour

Management

  • General
    • Treatment is not curative.
    • Outcome depends on
      • Performance score
      • Age
    • Minimum staging includes an MRI brain with either CT or CT PET of chest/ abdomen/ pelvis.
    • The whole patient and their cancer load must be considered, not just the brain metastasis
    • If the treatment is not working, consider malignant meningitis.
    • In patients with a history of cancer, a new brain lesion can still be a different cancer or an abscess.
  • Aim
    • Improve local control
    • Extend life
    • Prevent further neurological complications.
  • Steroids
    • Oral or intravenous corticosteroid therapy (dexamethasone)
    • Can dramatically reduce the symptoms caused by a tumour’s vasogenic oedema.
    • Dosage
      • Initial: 16 mg per day in two or four divided doses but should be tapered as fast as tolerated.
    • Side effects
      • Peptic ulceration
        • Ppi cover
      • Insomnia
      • Myopathy
      • Weight gain
      • Psychosis
      • Skin thinning
      • Cushing’s syndrome
      • Adrenal suppression
      • Increased risk of infection.
  • BEST tx plan: Surgery + SRS or SRS alone

Surgery: Focal treatment

1st Surgery
Aims
  • Provides diagnostic tissue,
  • Relieves mass effect
  • Is considered for solitary or oligometastatic disease.
Indication for aggressive surgery or SRS
  • Young <40
  • KPS>70
  • <4 brain met
  • Primary cancer is under control
  • Expected long disease free interval
  • Absence of leptomeningeal involvement
Evidence
  • Patchell 1990 (for single met) Surgery + RT vs RT → this is old use the Churilla 2019 data instead
        • Features
        Surgery + RT
        RT
        Recurrence at the site of the original metastasis
        20%
        52%
        Overall length of survival
        40wks (10 months)
        15wks (4 months)
        Functionally independent
        38 weeks
        8 weeks
  • Hart et al., 2005 Surgery + WBRT vs WBRT
    • Meta- analysis of 3 randomized controlled trials
    • No difference in survival
    • Surgery + WBRT increased the duration of Functionally Independent Survival (HR 0.42)
  • Krist 2022 (meta-analysis)
    • There was no difference in
      • Survival between surgery ± SRS versus SRS alone two years after treatment (OR 1.89 (95% CI: 0.47–7.55, P = .23)
      • Surgery + WBRT versus radiotherapy alone (either WBRT and/or SRS) (OR 1.18 (95% CI: 0.76–1.84, P = .46).
    • Surgical patients demonstrated greater risk for local tumour recurrence compared to SRS alone (OR 2.20) and compared to WBRT/SRS (OR 2.93)
    • Churilla 2019 Surgery VS SRS
      • This was study use in Krist 2022 meta-analysis
      • This is a secondary analysis of the Kocher 2011.pdf
      • Similar
        • Median Overall survival = 15 months
              • Cumulative incidences of death due to any cause according to SRS and surgical resection
              Cumulative incidences of death due to any cause according to SRS and surgical resection
        • local recurrence
      • Surgical resection had a much higher risk of early (0-3 months) local recurrence
        • The risk of recurrence decreased with time (HR for 3-6 months, 1.37 [95% CI, 0.64-2.90]; HR for 6-9 months, 0.75 [95% CI, 0.28-2.00]).
        • At 9 months or longer, the surgical resection group had a lower risk of local recurrence (HR, 0.36; 95% CI, 0.14-0.93).
Adjunct
  • Awake surgery
  • Integrated multimodal MRI studies
  • Image guidance
  • Radiotherapy
    • Conventional radiotherapy
    • SRS
  • Brachy therapy (Chitti 2020)
    • Agents
      • 125I seed
        • Offers rates of local control and overall survival comparable to standard of care modalities such as SRS.
          • Dagnew et al 2007: retrospective
            • Permanent 125I brachytherapy applied at the initial operation without WBRT provided excellent local tumour control.
            • Local control (96%) and patient survival rates (Median survival 17.8 months) were at least as good as those reported for resection combined with WBRT.
            • Higher incidence of distant metastases compared with that reported in other studies of initial WBRT
        • Radiation necrosis and regional recurrence were often high
      • 131Cs seed
        • Similar local control and survival benefits to 125I,
        • Low rates of radiation necrosis.
      • Photon radiosurgery
        • Superior regional control as compared to SRS,
        • Worse local control and higher rates of radiation necrosis than 125I
    • Not used widely because
      • The status of brachytherapy as an invasive procedure necessitating hospitalization
      • The absence of radiation oncologists’ or neurosurgeons’ expertise in brachytherapy;
      • The lack of published data on treatment outcomes; 4) The increasing role of stereotactic radiosurgery, which is a minimally invasive procedure used to treat many of the same tumors that can be treated with brachytherapy
  • Fluorescence guidance of met resection
    • Schebesch et al 2023 (MetResect study)
      • Fluorescein sodium (FL) accumulates in brain regions with a disrupted BBB
      • Technique
        • 5 mg of FL 10% (ALCON) per kilogram of body weight after the induction of anesthesia via a central venous line approximately 30–45 minutes prior to skin incision
        • Uses a YELLOW 560 nm filter
        • Unintended resection of false-positive fluorescence due to iatrogenic damage of the BBB was prevented by covering the resected surgical area with cotton
      • Fluorescence causes
        • Postoperative tumor volume was significantly smaller (p = 0.01),
        • OS was significantly longer: 2.6 months extra
Disadvantages
  • Remain the
    • Risk to life
    • Infection
    • Neurological disability
Surgical techniques
  • en bloc metastectomies
  • Supramarginal metastectomies
  • Carmustine wafers (Gliadel) implanted in the cavity following surgery have been reported to reduce local recurrence (Abel et al., 2013) but are rarely used.
SRS vs Surgery
  • In UK clinical practice, SRS is reserved for treating 1– 3 smaller tumours (with an upper limit of 20 cc or 30 mm diameter), where there is little oedema or mass effect and the patient is expected to survive 6 months.
      Features
      SRS
      Neurosurgery
      Duration
      Faster
      Slower
      Radioresistant tumours
      partially suitable
      Suitable
      Day case/No craniotomy
      Yes
      No
      GA/Can be done in comorbidity
      No
      Yes
      Decompression
      No
      Yes
      Post fossa met
      No
      Yes
      Tissue diagnosis
      No
      Yes
      Lesion limit
      <4cm
      Any size
      Suitable for Cystic lesions
      No
      Yes
  • Franzin et al., 2008: a combined approach with surgical cyst drainage and SRS has proved effective
  • In the future, hybrid approaches with combinations of surgery for the larger tumour plus SRS, interstitial laser thermal therapy, or MRgFUS., for smaller inaccessible lesions could become standard unless significant improvements in chemotherapy and immunotherapy occur.
2nd surgery (reoperation)
  • 2nd surgery may improve clinical status and over all survival but does carry a high complication rate
    • Choose patient carefully with Bindal's scoring system (esp KPS)
  • bindal 1995.pdf n48 retrospective study
    • Median time from first craniotomy to diagnosis of recurrence (time to recurrence) was 6.7 months
    • Median survival time after reoperation was 11.5 months
    • Grading system
        • Factor Evaluated
        Score
        Status of systemic disease
        ㅤ
        Present
        1
        Absent
        0
        Preoperative KPS score
        ㅤ
        ≤70
        1
        >70
        0
        Time to recurrence
        ㅤ
        <4 mos
        1
        ≥4 mos
        0
        Age
        ㅤ
        ≥40 yrs
        1
        <40 yrs
        0
        Type of primary tumor
        ㅤ
        Melanoma or breast
        1
        Lung or other
        0
        notion image
      • Grade 1 >50% surviving > 5 yrs
      • Grade 4 Less than one year Survival
  • Heßler 2022 n107 retrospective
    • Complication rate was 26.2%
    • Two patients died during the perioperative period.
    • Median postoperative
      • Event-free survival 7.1 months
      • OS 11.1 months
    • The clinical status (postoperative KPS ≥ 70 (HR 0.27 95%CI 0.16–0.46; p < 0.001) remained the only independent factor for survival in multivariate analysis.

Radiotherapy

General
  • Both surgery and SRS have a proven survival benefit in the management of a single brain metastasis.
  • Typically, surgery is preferred in patients with good performance status, large lesions (> 3 cm), or symptomatic tumors with substantial vasogenic edema.
  • In patients who are good candidates for either surgery or SRS, there are no randomized data currently available to indicate which is the preferred treatment modality.
  • In general, the current debate regarding patients with multiple metastases surrounds whether to use WBRT, SRS, or both.
  • Survival, recurrence, focal neurological deficit and neurocognitive outcome are key considerations.
Fractionated radiotherapy
  • Brown et al., 2013: may reduce cognitive harm by
    • Hippocampal sparing,
    • Using reduced whole brain fields while boosting the tumour bed, or by using neuroprotective agents such as memantine
SRS (Stereotactic radiosurgery)
  • A form of ionizing radiation therapy that focuses high- powered energy on a small target in a single or a few fractions.
  • Indications for SRS:
    • Oligometastases (1-3) or multiple (4-10) metastases especially if primary tumor is known to be radiotherapy resistant
    • Postsurgical resection of a single BM, especially if 3 cm or bigger and in the posterior fossa
    • Local relapse after surgical resection of a single brain metastasis
    • Salvage therapy for recurrent oligometastases (1-3) after WBRT
  • Any form of radiation reduces local recurrence but radiation does not necessarily improves survival
  • Advantages
    • Can be done as a day case
    • Can use a thermoplastic mask rather than a frame
    • Avoids any surgical procedure
    • Can target multiple lesions in deep or eloquent cortex
    • Has results comparable to surgical series.
    • Highly targeted therapy spares normal brain tissue and preserves neurocognitive function
  • Limitations
    • Lesions need to be typically < = 4 cm (RTOG) and Max intracranial disease < =20 cm3 (NICE)
      • Radiation necrosis rates increase with increasing tumour volume irradiated
        • Hypofractionated regimes for lesions larger than 20 cm3 may be used.
    • Lesions cannot be abutting the optic nerves or brainstem due to risk local radionecrosis
    • Cystic and radioresistant tumour (commonly renal and melanoma) lesions respond less well.
    • Less suitable for Post fossa met
      • Tumours can swell after treatment leading to extended steroid treatment and concomitant side effects
    • No tissue diagnosis.
    • SRS will not treat the invisible micrometastatic foci which will grow to cause neurological deterioration later on
  • There are no certain efficacy or safety differences between the different platforms available
    • Gamma knife
    • Cyberknife
    • Linear accelerator
  • Post op SRS
    • Pros
      • To treat microscopic tumor extension.
  • Pre op of SRS
    • Pros
      • Reduces the potential for tumor seeding at the resection site and in the cerebrospinal fluid, which may prevent local recurrence and nodular leptomeningeal spread
      • (Cheok et al 2023) Minimizing collateral radiation to the surrounding normal brain parenchyma.
    • No published improvement in OS yet
  • Advanced MRI (e.g. DWI) prediction of microscopic infiltration and tumour residual could be used in the future to try to improve SRS planning and treatment selection.
  • Evidence
    • Yamamoto 2012.pdf N1194
      • Largest tumour <10 mL in volume and <3 cm in longest diameter; total cumulative volume ≤15 mL
      • SRS only for pt with <4 vs >4 brain mets
      • No difference in overall survival, complications, and local recurrence
    • Brown 2017.pdf N194
      • SRS vs WBRT
      • Decline in cognitive function was more frequent with WBRT
        • Cognitive deterioration at 6 months
          • SRS 52%
          • WBRT 85%
            notion image
      • No difference in overall survival between the treatment groups. (Approx 12 months)
            • notion image
      • Post op SRS should be considered one of the standards of care as a less toxic alternative to WBRT for this patient population.
Whole- brain radiotherapy (WBRT),
Indications for WBRT:
  • CNS and systemic progression of disease, with few systemic treatment options and poor performance status
  • Multiple (4-10) brain metastasis especially if primary tumor known to be radiotherapy sensitive (NB current data support SRS use in up to 3 metastasis but there is a growing trend to use it in up to 10)
  • Large (> 4 cm) brain metastasis not amenable to SRS
  • Postsurgical resection of a dominant hemisphere brain metastasis with multiple (4-10) remaining BMs
  • Salvage therapy for recurrent BM after SRS or WBRT failure
Pros
  • WBRT improves survival and tumour control in the brain
  • SRS will not treat the invisible micrometastatic foci which will grow to cause neurological deterioration later on
Limitations
  • Cognitive harm.
    • 90% of patients with brain metastases have impaired neurocognitive function at diagnosis
    • Pinkham et al., 2015: 2/3 will show further decline within 2– 6 months of WBRT
    • Omitting whole- brain radiotherapy after local therapy increases the time until cognitive decline and improves verbal memory but it is argued that progression and the associated salvage treatments outweigh any benefit that has been gained
    • Numbers
      • Cognitive impairment at 12 months is 12% in control and 41% in prophylactic cranial irradiation (30 Gy)
      • Cognitive impairment at 12 months is 62% for 25 Gy and 85% for 36 Gy prophylactic irradiation
      • Cognitive impairment at 4 months is 24% in SRS alone vs 52% in SRS + WBRT
Dose
  • Standard
    • 20Gy in 5 fractions
    • 30 Gy in 10 fractions
  • Prolonged regiment
    • 40Gy = 2Gy in 20 sessions
    • Try to reduce radiation complications
    • For pt with longer life expectancy >1 yr
Radio sensitivity
  • Highly Resistant T MRSA (Uses SRS)
    • Malignant melanoma;
    • Renal-cell carcinoma;
    • Thyroid cancer;
    • Sarcoma;
    • Adenocarcinoma
  • Moderately resistant
    • Breast Ca
  • Moderately sensitive
    • Colorectal cancer;
    • Non small-cell lung cancer.
  • Highly Sensitive MLS GoaL
    • Small-cell lung cancer;
    • Germ-cell tumors;
    • Lymphoma;
    • Leukemia;
    • Multiple myeloma
Evidence
  • Mulvenna et al., 2016
    • WBRT does not improve survival in all patients
    • Esp:
      • In those older patients with NSCLC,
      • Poor performance score
    • Better to use
      • Simple steroid treatment
      • Good palliative care may be more appropriate
  • Patchell et al., 1998 → use Kocher 2011 data instead. surgery + WBRT (n = 49) VS surgery (n = 46),
    • The addition of WBRT
      • Improved intracranial control from 30% to 82%
      • Reduced local recurrence 18% vs 70% (Surgery only)
        • Associated with increased neurological death
    • No difference in
      • Overall survival
      • Quality of life (in the form of time spent in good performance status)
  • Kocher 2011.pdf n359
    • Bottomline:
      • After SRS or surgery of a limited number of brain metastases, adjuvant WBRT reduces intracranial relapses and neurologic deaths but fails to improve the duration of functional independence and overall survival
        • Quality of life data from this trial found that WBRT caused poorer physical functioning and fatigue at 8 weeks, worsening global health status at 9 months, and deteriorating cognitive functioning.
        • Surgery + WBRT vs Radiosurgery + WBRT vs Surgery + observation vs Radiosurgery + observation
        • WBRT reduced the frequency of recurrence in the resection bed from 60% to less than 30%
          • Intracranial progression caused death in 78 (44%) of 179 patients in the OBS arm and in 50 (28%) of 180 patients in the WBRT arm
        notion image
    • SRS + WBRT
      • No difference in overall survival
      • Intracranial progression causing death was reduced from 44% to 28% and fewer salvage therapies were required.
  • Tsao et al., 2012
    • Meta- analysis
    • WBRT + SRS improves local control but not overall survival
    • Recommended omitting WBRT due to the deleterious cognitive effects

Interstitial laser therapy

  • Passes a laser through a burr hole to heat up tumours, controlled by almost real- time MR thermography

Focused ultrasound treatment

  • MRguided focused ultrasound (MRgFUS) uses ultrasound, controlled with MR thermography, to target deep seated lesions.
  • Initially used for fibroids, MRgFUS is starting to be used for cranial lesions (Coluccia et al., 2014).

Chemotherapy

  • Targeted or immune therapies
    • Areas under investigation include identifying antimetastasis effects among agents that cross the blood– brain barrier (BBB), developing agents that act systemically to prevent brain metastases occurring and facilitating traditional chemotherapy agents to cross the blood– brain barrier.
    • Melanoma
      • Jones et al., 2015
        • Pretreatment with the immunotherapy agent ipilimumab improved the effects of surgery
      • Goyal et al., 2015:
        • In the 50% of patients with a B- Raf Proto- oncogene (BRAF) mutation, inhibiting the pathway can extend overall survival (> 7 months) for patients with untreated brain metastases
    • Breast or lung Ca
      • A new UK study (CAMBT1) of a tyrosine kinase inhibitor for patients undergoing resection of lung or breast metastases is testing whether low- dose, targeted radiotherapy to the metastasis preoperatively improves drug penetration.

Palliative care

  • Specific problems include cognitive decline, poor mobility, thromboembolism, pain, reduced self- care, anxiety, depression, and epilepsy (Taillibert and Delattre, 2005).
  • Early involvement of palliative care teams is essential to maximize a patient’s quality of life.
  • Post op Seizure risk
    • Cummins et al 2023: CDKN2A alterations and melanoma primary malignancy are associated with increased postoperative seizure risk following resection of BMs.

Indications for different treatment modalities

  • Consider chemotherapy/biologics in brain metastasis:
    • From highly chemotherapy-sensitive primary tumor
    • Asymptomatic/found on screening MRI with planned systemic therapy
    • Primary tumor with identified molecular alteration amenable to targeted therapy
    • Other options exhausted and there is a reasonable drug available
  • Consider WBRT in brain metastasis when:
    • CNS and systemic progression of disease, with few systemic treatment options and poor performance status
    • Multiple (4-10) brain metastasis especially if primary tumor known to be radiotherapy sensitive (NB current data support SRS use in up to 3 metastasis but there is a growing trend to use it in up to 10).
    • Large (>4 cm) brain metastasis not amenable to SRS
    • Postsurgical resection of a dominant hemisphere brain metastasis with multiple (4-10) remaining BMs
    • Salvage therapy for recurrent BM after SRS or WBRT failure
  • Consider SRS when:
    • Oligometastases (1-3) or multiple (4-10) metastases especially if primary tumor is known to be radiotherapy resistant
    • Postsurgical resection of a single BM, especially if 3 cm or bigger and in the posterior fossa
    • Local relapse after surgical resection of a single brain metastasis
    • Salvage therapy for recurrent oligometastases (1-3) after WBRT
  • Consider surgical resection when:
    • Uncertain diagnosis of CNS lesion(s)
    • 1-2 BMs, especially when associated with extensive cerebral edema
    • Dominant BM in a critical location
  • No treatment is reasonable when:
    • Systemic progression of disease with few treatment options and poor performance status
Table with permission from Lin X, DeAngelis LM. Treatment of Brain Metastases. J Clin Oncol. 2015;33(30):3475-3484.

Reference