Eric Chang, MD, a radiation oncologist at Keck Medicine of USC, discusses the latest evidence-based approaches in the treatment of metastatic brain disease, including the evolving role of radiosurgery, fractionated stereotactic radiation, whole-brain radiation and emerging targeted therapies.
Yeah. Good afternoon. My name is Dr Eric Chang and I am the head of the Department of Radiation Oncology at the Keck School of Medicine. The title of my talk today is indications for whole brain radiation therapy versus radiosurgery in the management of multiple brain metastases. The learning objectives for today are to review the role of SRS vert Visa vee whole brain radiotherapy and the management of brain metastases, and to review some current trends related to brain metastases management. Like the outline, My talk, where we'll begin with a background with some demographic trends of brain metastases will go through some key randomized trials and also review toxicities of modalities. And then finally, we'll close with future directions. So this is a recent illustration showing the relative incidents of various, uh, brain metastases from different primaries such as lung cancer, breast cancer, we know cell carcinoma, melanoma and colorectal, or G ay, cancer. Where lung cancer is the most common cancer in terms of the relative incidents of brain metastases, I'd like to forecast evolving relative rolls of whole brain radiation therapy and radio surgery, where we are seeing a, uh, continual and persistent decline in the utilization of whole brain radiation therapy. While we're seeing an increase in the utilization of radio surgery due to more sophisticated technology, more targeted therapies in the advent of additional randomized trials showing support for radio surgery. Of course, there are patients with low performance status left the men in jail disease and uncontrolled disease who will still be candidates for whole brain radiation therapy. This slide shows you the demographics of the aging baby boomer population, where the proportion of of of people who are seniors is rising according to each decade. And what this aging demographic indicates to us is that there will be an increase incidents of of new cancer cases and therefore an increasing incidents of metastatic brain disease development. This is a slide showing you the number of metastatic patients treated worldwide from 1968 to 2010. It's showing you a cumulative incidence of patients treated with Lex L. Gamma Knife Treatment, which is a surrogate for all patients being treated with radio surgery. These air guidelines released by the SRS organization for patients with 1 to 4 brain metastases, uh, showing various, uh, key clinical trials. Addressing the question of management of 1 to 4 brain metastases with radio surgery alone or radiosurgery plus whole brain radiation. A trend to be aware of is that Mawr effective systemic therapies may be translating into increase CNS metastases, in particular women with her two positive breast cancer. The widespread use of her two directed therapy with trans twosome Mob has unmasked a population in whom CNS progression is a significant source of morbidity and mortality. Since tries to sin mob does not penetrate the CNS. What is effective outside the CNS? While whole brain radiation therapy comprehensively treats the brain, it doesn't eliminate all brain metastases. This is shown dia grammatically, where brain all brain metastases are treated with whole brain radiation therapy, and you can see a subset of the lesions are able to break through the whole brain. British therapy treatment requiring post whole brain um, treatment in the terms of salvage treatment or some type of palliative therapy. Sophisticated platforms do increase access and efficiency of radiosurgery treatments. This is an example of the wide variety of platforms that are available to treat metastatic brain disease. Today, the issue is that technological feasibility versus evidence based practice leads us to questions about how best to utilize this technology. Current sophisticated rate of surgery units allowed treatment of a large number of brain metastases in a single session with greater efficiency than was previously possible. This newfound capability begs the question. Just because the technology allows us to treat greater than four lesions doesn't mean that we should. So the challenge is performing and completing next generation randomized trials for 4 to 15 brain metastases. Such a trial is currently ongoing and stratified patients. According Thio intracranial volume, number of lesions and histology patients were randomized the whole brain radiation therapy or radiosurgery alone. This is the Canadian Cancer Trials Group trial, which opened in 2018, which stratified patients according to number peacock status size and volume. Um, patients were stratified, according to DS g p A use of targeted or immunotherapy rated surgical system, or histology and randomized to reduce surgery or whole brain British therapy, plus my man team. So this volume of Matassa these matter is it better toe? Have five small brain metastases or one very large brain metastases following probably does matter and may even be more important than the number of lesions. This is a paper from the University of Pittsburgh, which looked at four or mawr intracranial metastases and found that for patients fitting into this scenario, total treatment volume was the most significant predictor of survival. So let's do a treatment. Toxicity comparison potential radiosurgery toxicities include rare acute toxicities such as headaches, nausea, vomiting, aphasia, motor neuropathy, seizure, swelling and hemorrhagic stroke, as well as rare late toxicities such as radiation necrosis, radiation associated, secondary malignancies and death. Although this is extremely rare potential, whole brain rage therapy toxicities include New York cognitive deficits, permanent alopecia skin erythema, hyperpigmentation, taste alteration, fatigue, otitis media zero Estonia, Psycho motor, slowing Leuco and several off the radiation recall with chemotherapy and concurrent chemo. Whole Grain British Therapy, which is ill advised the M the M D. Anderson randomized clinical Trial schema, which I lead when I was there and was presented at the Astra plenary session in 2000 and eight stratified patients According to our P, a class number of lesions in histology patients were randomized to receive either radiosurgery plus whole brain radiation therapy or radiosurgery alone. Primary endpoint of this trial was cognitive decline in learning and memory. The Hopkins verbal learning test, which was the primary endpoint, was used to measure decline and learning and memory by detecting ah five point or greater drop four months from baseline. The results showed of this study that patients were randomly assigned to receive SRS plus whole brain. British therapy had approximately twice the probability of developing neurocognitive deficits as measured by the H B L T test, about 50% in the whole brain British therapy arm and 25% for patients who were randomly assigned to the SRS Onley arm. Study conclusions were that SRS plus whole brain patients were at greater risk of significant decline in learning and memory function by four months compared to the group that received Greater Sergi alone. Initial treatment with combination 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. So what is close clinical monitoring mean according to the N c C n. This means brain memorize every 2 to 3 months for the first year and then every 4 to 6 months indefinitely. Astra has released a choosing wisely position statement in 2014, indicating that the addition of whole brain to radio surgery is associated with diminished cognitive function and worst patient reported fatigue and quality of life. These results are consistent with the worst in self reported cognitive function. A diminished verbal skills observed in randomized studies, a prophylactic created radiation for small cell or non small cell lung cancer. What now? Let's look at radiosurgery for single brain metastases and in the probability of achieving tumor control. This is a study that was done at the Cleveland Clinic, involving 200 to patients with 375 lesions treated between 1997 2003. The one year local control rates by margin dose were for 24 grade 85%. 18 gray, 49% of 15 gray, 45%. The hazard ratio for local failure was 0.277 This shows you graphically the time the local failure stratified by dosage. So the take home message from this is that what the higher doses and therefore very small lesions one can expect fairly good control rates of lesions treated with radiosurgery. However, for patients who are treated with 15 to 18 gray for intermediate or larger lesions. The outcomes are somewhat unsatisfactory. Now. Coming evaluation of patients treated with fractionated again when I've read of surgery for large brain metastases was performed and a dose escalation studied by Kim at all. This is showing you the waterfall plots where the the reddish bars indicate progression and the green bars indicate response or stay stable lesions. And these were divided into groups such as eight grade perfection, nine grade perfection and 10 grade perfection. You can see fairly robust responses and changes in tumor volume for these three dose levels. Next trial I'd like Thio discuss is the N C C T g n zero fivesome for alliance Study Phase three. Randomized Trial of Whole Brain Redish therapy in addition to radio surgery and patients with 123 brain metastases published in JAMA 2016, The background is that cognitive failure is which has a worst cognitive impact, tumor recurrence or whole brain radiation therapy. The design of this trial was such that patients with brain metastases were stratified according to age extra cranial disease, number of brain metastases, and institution and randomized to radio surgery or radiosurgery, plus whole brain. The primary objective was to determine if cognitive progression at three months post radiosurgery is less with radiosurgery alone than SRS. Combined with whole brain radiation therapy, primary endpoint his cognitive progression at three months. These are the results. Cognitive progression at three months, measured by a variety of cognitive tests, showed that patients randomly assigned to radiosurgery had a 63.5% rate of cognitive progression. Patients randomly assigned to SRS plus whole brain had a 91.7% rate of cognitive progression at three months, and this was highly statistically significant, with a P Valley A 0.7 So decline and cognitive function was more frequent with the addition of whole brain toe, as seen by the M. D. Anderson trial, which was discussed earlier, thus confirming the results from that earlier trial. This persisted at six months and was statistically significant. Long term survivors, although not statistically significant, you can see that there is a trend with the SRS bars in blue on the SRS plus whole brain radiation therapy patients in orange, and you can see that the orange are trending lower than the blue bars. So in conclusion, this study found that decline and cognitive functions more frequent with the addition of whole brain reach therapy to radiosurgery, specifically an immediate recall memory and rebel fluency. Now these Air Companion randomized postoperative trials. This is the N 107 c trial, which was run by the N, C C T G and what What This trial, um, found was that for patients randomized to receive postoperative whole brain British, the therapy um, there was a greater rate of cognitive decline than in patients who had radiosurgery post operatively and the cognitive deterioration. Free survival was superior and patients who were randomly assigned to receive rate of surgery. However, the surgical bed control, um, was seen to be 60% a 12 months in the radio surgery patients and 80.6% in the whole brain radiation therapy patients. This is a surprising result because one would expect that radiosurgery would be superior. Two whole brain British therapy. There are a number of reasons that can be postulated for this, which I will not go into in this talk. There's a companion post operative randomized trial, uh, done at M D. Anderson by Mahajan at all and colleagues What this trial showed that the freedom from local recurrence with superior for patients who got post operative radiosurgery compared to observation and what this The graph on the right shows is that for patients who had smaller tumors less than 2.5 cm, these had the highest control rates. Whereas for larger tumors, intermediate and larger tumors, the rates were not as good. I'd like to shift gears to part two of my talk looking at whole brain British therapy for brain Matassa. These the indication is dependent on the spectrum of brain metastases. Volume case one we can consider has no visible brain metastases. This would be administering prophylactic cranial radiation case to would be small volume disease 1 to 10 brain metastases in case three would be greater than 10 plus brain metastases for for case one, would we give prophylactic cream radiation to most, um, brain metastases primaries excluding small cell lung cancer. The answer is no. We would not do this for Case two. Would we do radiosurgery for 1 to 10 brain metastases? The answer is yes. And for case three for greater than 10 brain metastases, we would individualize. This is the PC trial run by the Rto G 0 to 14 for non small cell lung cancer on what they showed was that observation or PC, I showed no difference in overall survival and disease free survival. However, there was an increased rate of CNS metastases failure. The patients randomly assigned to the observation arm Deterioration of Hopkins Verbal Learning Test with P C I for non small cell lung cancer can be seen. You can see at three months you can see the rate is 46% versus 13% in recall. And then this persists at 12 months for 26% in the P C I armed versus 7% in the observation arm. Both differences air statistically significant. This is showing you graphically how you can see the effects of the PC I at three months. And then there's a rebound. And then there's the effect again at 12 months. Next, trialist the European trial, looking at radio surgery or surgery, plus or minus whole brain for +123 brain metastases. Small volume disease. Should we give SRS plus whole brain British therapy? Maybe. What this trial found was that, um, time to inter cranial progression at news sites was improved with whole grain rage therapy. And, um, it showed that for patients who had, uh, surgery performed and had observation, um, there was a approximately 50% rate of local recurrence, Um, that you can see in panel B in the yellow curve. On that, this rate was decreased significantly with the addition of whole brain British therapy. I think the take home point from this data is that you cannot just do surgery alone and that it needs to be followed up with some adjuvant therapies, such as whole brain radiation therapy. In this example, survival with W H O performance score less than or equal to was the same in both arms. They track the same, and overall survival was also the same between observation or achievement. Whole grain radiotherapy What is the maximum number of newly diagnosed brain metastases that should be treated with radiosurgery? This is a moving target. It's unknown. This is a paper by the Japanese group led by Yamamoto and colleagues published in Lancet oncology, showing that for patients treated at multiple Gammon I centers in Japan, patients with one tumor had the best outcome. Patients were then categorized according to 2 to 4 and 5 to 10, tumors. Prospectively, this is non randomized data and showed that the outcome was about the same between 2 to 4 and 5 to 10 tumors, thus arguing for doing rate of surgery for greater than for brain metastases. Up to 10 metastases. This is a paper by Hughes published in The Red Journal in 2019, looking at one versus 2 to 4 and 5 to 15. Looking at the survival probability. And like the Yamamoto paper, you can see that patients did best in the single brain metastases group. However, for patients with 2 to 4 or 5 to 15 lesions, these patients had a very similar survival rates. This is just a case illustration. Looking at a 35 year old patient with E g f are positive lung cancer with 34 metastases with a medium volume 0.26 CCS. A total GT volume of four CCS. All targets were able to be treated in six sessions over eight days. Fossil maybe 3 to 7 targets were treated each day using a prescription dose of 18 gray to 32 targets and 16, grade 22 targets. A total of 45 shots were used. Most of the targets were treated with a single shot. So this is showing you just the technical capability of being able to treat a number of high lesions. Now, this is the same group by Yamamoto, uh, looking at a multi institutional prospective observational study of stereotyped radiosurgery for patients with multiple multiple brain metastases. And this is looking at the mini mental state examination scores, which shows that most of the patients one versus 2 to 4 versus 5 to 10. We're about 86 to 80 88% preserved out to a number of months. 48 months. Creation related complications were about 15% or less, and then the rate of Luke and Steph philosophy was low at less than 1%. This last trial I'd like to present you is a trial from Australia and multiple other centers led by Dr Hong, looking at Agilent whole brain radiotherapy versus observation after local treatment of 123 melanoma brain metastases, multi center randomized face retrial. This trial is in is unique and that it focuses exclusively on melanoma patients, whereas most trials include patients coming from non small cell lung cancer. This is a histology specific based randomized trial In this trial, 123 brain Matassa he's seen on Emery were treated with either surgery and or radiosurgery. They were stratified according to age, sex, number of lesions, presence or absence of extra cranial disease and plant rt dose. Patients randomized to receive whole brain British therapy or observation and follow up on outcome. Assessments were performed until withdrawal or death, and three months and three month memories were also performed. Any systemic therapy was permitted. There was center of radiologic review and there is quality assurance performed on the whole brain radiation therapy. Primary endpoint of the study was distant intracranial control at 12 months. Secondary endpoints included local intracranial failure, overall survival, time to deterioration, quality of life, neurocognitive function and health economics. Patients were accrued from 24 sites, including Australia, Norway and the UK. From April of 2009 to September 2017, 935 patients were assessed eligibility. Ultimately, 215 patients were randomized, 107 to the whole grain radiotherapy group and 108 to the observation group. primary endpoint analysis was performed in 101 107 patients respectively. Thes air the patient characteristics ah 100. About 100 patients had one lesion, 40 patients had two lesions and 14 patients had three lesions in the whole brain arm, whereas in the observation arm, 107 had one lesion, 41 had two lesions and 15 had three lesions. Distant intracranial failure was shown as district intracranial failure incidents in this figure showing there was 42% rate of intracranial failure distantly in the whole brain radiotherapy arm and 50.5% in the observation arm. This numerical difference did not re see did not reach statistical significance. With a P value of 0.16 the H R or hazard ratio is 1.28 crossing unity between 0.89 and 1.84 Distant intracranial failure was also looked at according to systemic therapy primary endpoint, the whole brain radiotherapy arm receiving um effective systemic therapy is in solid blue and then the observation arm receiving effective systemic therapy is in solid orange. You can see the results here thes air not statistically significant local intracranial failure. Initial site of brain metastases is shown and there is a rate of 20% in the whole bring radiotherapy arm at 12 months and 33.6% The observation arm reading reaching borderline significance at a P value of 0.5 Time to deterioration in peacock performance status is very similar and you can see that the two curves track with each other with a P value of 0.32 Overall survival was very similar, 58% versus 54% not statistically significant. Log rank P values 0.89 with 45% neurological debts. The study concluded that achievement whole brain radiotherapy does not improve intracranial control, survival or performance status after local treatment of 123 melanoma brain metastases for single brain metastases. Better local control was seen with whole brain radiation therapy. The same could be achieved with cavity radiosurgery. Close observation while undergoing systemic therapy seems to be the preferred uh, approach on. This is the first completed single histology agreement. Whole grain read a therapy trial. The argument for using whole brain radiotherapy to treat occult microscopic disease is diminished by the use of immunotherapy and immune checkpoint inhibitors for brain metastases. I present to you this trial looking at combined no volume mob and the mob in melanoma, metastatic to the brain, presented by Talebi and the New England Journal of Medicine. What you can see is that in the swimmers plot is that there are a number of patients who did quite well and there was only progression in three cases. You can also see the Kaplan Meier estimates of survival here at 12 months, which is quite favorable. Lastly, I'd like to leave you with future therapies. This is a illustration showing the various potential targets that could be targeted and treating various patients with differing, uh, histology ease their our target opportunities for for targeted therapy in the future that hopefully can be combined with the current conventional treatments. The last trial I'd like to leave you with is a unique, biomarker driven trial and brain metastases, which looks at progressive brain metastases and histological confirmed solid malignancy measurable CNS disease. Um, and there are actionable alterations in C d K pathway pi three Kindness, a K, T or M, Tor Pathway and Alk and Trek or Ross one translocation. This trial is looking at lung, breast and other patients and is applying treatments such a seed kei inhibitor, P three kindness inhibitor or alk and Trek Ross inhibitor. Brain memories and systemic staging are performed every eight weeks until CNS or systemic progression. Thank you for your attention today. Mhm.