https://iris.unito.it/bitstream/2318/1677658/1/OP-ANNO180277%20192..237.pdf

Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up †

Promising results from new approaches such as radiosurgery or stereotactic radiosurgery of brain metastases have recently been reported. Are these results due to the therapy alone or can the results be attributed in part to patient selection? An analysis of tumor/patient characteristics and treatment variables in previous RTOG brain metastases studies was considered necessary to fully evaluate the benefit of these new interventions.

Recursive partitioning analysis (RPA) of prognostic factors in three radiation therapy oncology group (RTOG) brain metastases trials

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(04)16250-8.pdf

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

Summary Background It is unclear whether the benefit of adding whole-brain radiation therapy (WBRT) to stereotactic radiosurgery (SRS) for the control of brain-tumours outweighs the potential neurocognitive risks. We proposed that the learning and memory functions of patients who undergo SRS plus WBRT are worse than those of patients who undergo SRS alone. We did a randomised controlled trial to test our prediction. Methods Patients with one to three newly diagnosed brain metastases were randomly assigned using a standard permutated block algorithm with random block sizes to SRS plus WBRT or SRS alone from Jan 2, 2001, to Sept 14, 2007. Patients were stratified by recursive partitioning analysis class, number of brain metastases, and radioresistant histology. The randomisation sequence was masked until assignation, at which point both clinicians and patients were made aware of the treatment allocation. The primary endpoint was neurocognitive function: objectively measured as a significant deterioration (5-point drop compared with baseline) in Hopkins Verbal Learning Test–Revised (HVLT-R) total recall at 4 months. An independent data monitoring committee monitored the trial using Bayesian statistical methods. Analysis was by intention-to-treat. This trial is registered at www.ClinicalTrials.gov, number NCT00548756. Findings After 58 patients were recruited (n=30 in the SRS alone group, n=28 in the SRS plus WBRT group), the trial was stopped by the data monitoring committee according to early stopping rules on the basis that there was a high probability (96%) that patients randomly assigned to receive SRS plus WBRT were significantly more likely to show a decline in learning and memory function (mean posterior probability of decline 52%) at 4 months than patients assigned to receive SRS alone (mean posterior probability of decline 24%). At 4 months there were four deaths (13%) in the group that received SRS alone, and eight deaths (29%) in the group that received SRS plus WBRT. 73% of patients in the SRS plus WBRT group were free from CNS recurrence at 1 year, compared with 27% of patients who received SRS alone (p=0·0003). In the SRS plus WBRT group, one case of grade 3 toxicity (seizures, motor neuropathy, depressed level of consciousness) was attributed to radiation treatment. In the group that received SRS, one case of grade 3 toxicity (aphasia) was attributed to radiation treatment. Two cases of grade 4 toxicity in the group that received SRS alone were diagnosed as radiation necrosis. Interpretation Patients treated with SRS plus WBRT were at a greater risk of a significant decline in learning and memory function by 4 months compared with the group that received SRS alone. Initial treatment with a combination of SRS and close clinical monitoring is recommended as the preferred treatment strategy to better preserve learning and memory in patients with newly diagnosed brain metastases. Funding No external funding was received.

https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(09)70263-3.pdf

Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial.

ContextIn patients with brain metastases, it is unclear whether adding up-front whole-brain radiation therapy (WBRT) to stereotactic radiosurgery (SRS) has beneficial effects on mortality or neurologic function compared with SRS alone.ObjectiveTo determine if WBRT combined with SRS results in improvements in survival, brain tumor control, functional preservation rate, and frequency of neurologic death.Design, Setting, and PatientsRandomized controlled trial of 132 patients with 1 to 4 brain metastases, each less than 3 cm in diameter, enrolled at 11 hospitals in Japan between October 1999 and December 2003.InterventionsPatients were randomly assigned to receive WBRT plus SRS (65 patients) or SRS alone (67 patients).Main Outcome MeasuresThe primary end point was overall survival; secondary end points were brain tumor recurrence, salvage brain treatment, functional preservation, toxic effects of radiation, and cause of death.ResultsThe median survival time and the 1-year actuarial survival rate were 7.5 months and 38.5% (95% confidence interval, 26.7%-50.3%) in the WBRT + SRS group and 8.0 months and 28.4% (95% confidence interval, 17.6%-39.2%) for SRS alone (P = .42). The 12-month brain tumor recurrence rate was 46.8% in the WBRT + SRS group and 76.4% for SRS alone group (P<.001). Salvage brain treatment was less frequently required in the WBRT + SRS group (n = 10) than with SRS alone (n = 29) (P<.001). Death was attributed to neurologic causes in 22.8% of patients in the WBRT + SRS group and in 19.3% of those treated with SRS alone (P = .64). There were no significant differences in systemic and neurologic functional preservation and toxic effects of radiation.ConclusionsCompared with SRS alone, the use of WBRT plus SRS did not improve survival for patients with 1 to 4 brain metastases, but intracranial relapse occurred considerably more frequently in those who did not receive WBRT. Consequently, salvage treatment is frequently required when up-front WBRT is not used.Trial Registrationumin.ac.jp/ctr Identifier: C000000412

https://jamanetwork.com/journals/jama/articlepdf/202954/joc60064.pdf

Stereotactic Radiosurgery Plus Whole-Brain Radiation Therapy vs Stereotactic Radiosurgery Alone for Treatment of Brain Metastases: A Randomized Controlled Trial

Most patients treated for single or multiple brain metastases die from progression of extracranial tumor activity. This makes it uncertain whether the combination of neurosurgery and radiotherapy for treatment of single brain metastasis will lead to better results than less invasive treatment with radiotherapy alone. The effect of neurosurgical excision plus radiotherapy was compared with radiotherapy alone in a prospectively randomized trial with 63 evaluable patients with systemic cancer and a radiological diagnosis of single brain metastasis. Radiotherapy was given to the whole brain by a novel scheme of 2 fractions per day of each 2 Gy for a total of 40 Gy. Before randomization, patients were stratified by site (lung cancer vs nonlung cancer) and status of extracranial disease (progressive vs stable). Survival as such and functionally independent survival (FIS; defined as World Health Organization performance status < or = 1 and neurological function < or = 1) were compared between both treatment arms. The combined treatment compared with radiotherapy alone led to a longer survival (p = 0.04) and a longer FIS (p = 0.06). This was most pronounced in patients with stable extracranial disease (median survival, 12 vs 7 mo; median FIS, 9 vs 4 mo). Patients with progressive extracranial cancer had a median overall survival of 5 months and a FIS of 2.5 months irrespective of given treatment. Improvement in functional status occurred more rapidly and for longer periods of time after neurosurgical excision and radiotherapy than after radiotherapy alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of single brain metastasis: Radiotherapy alone or combined with neurosurgery

Purpose: To determine if in patients with single brain metastasis the addition of neurosurgery to radiotherapy leads to lengthening of survival or to better quality of life. Methods and Materials: From 1985 to 1990, 66 patients with single brain metastasis from a solid tumor were entered in a randomized trial of neurosurgery plus radiotherapy vs. radiotherapy alone. Patients were stratified for lung cancer vs. other sites of cancer and for progressive vs. stable systemic cancer. Radiotherapy was given to the whole brain by a novel scheme of two fractions of 2 Gy per day for a total dose of 40 Gy in 2 weeks, to obtain a relatively high total dose and short overall time, with minimal risk of late damage to normal tissue in long-term survivors. Results: In the whole group of 63 evaluable patients, both with lung cancer as with other tumors, the combined treatment led to a better duration of survival (median 10 vs. 6 months; p = 0.04). The largest difference between both treatment arms was observed in patients with inactive extracranial disease (median 12 vs. 7 months; p = 0.02). Patients with active extracranial disease had an equal median survival of only 5 months, irrespective of given treatment. Age proved to be a strong and independent prognostic factor: patients older than 60 years had a hazard ratio of dying of 2.74 (p = 0.003) compared with younger patients. Following treatment, most patients remained functionally independent until a few weeks before death. In the majority of patients the cause of death was systemic tumor progression. Conclusion: Patients with single brain metastasis and with controlled or absent extracranial tumor activity should be treated with surgery and radiotherapy, especially when they are younger than 60 years. For patients with progressive extracranial disease, radiotherapy alone seems to be sufficient. The accelerated radiotherapy scheme of 40 Gy in 2 weeks to the whole brain is tolerated well and should also be considered for patients in a good performance status with surgically unaccessible single metastasis or even with multiple brain metastases.

A. R. Wattendorff

Papers

Treatment of single brain metastasis: Radiotherapy alone or combined with neurosurgery

The choice of treatment of single brain metastasis should be based on extracranial tumor-activity and age