Brain Metastases

In a culmination of over 10 years of research effort, dating back to original observations that the hippocampus in rodent pups is an exquisitely radiosensitive structure, and central to the generation of memory-forming neurons from an innate radiosensitive stem cell compartment, Gondi et al have produced level I evidence of its seminal role in humans. In the plenary session at the SNO 2018 Annual Meeting (Society for Neuro-Oncology 23rd Annual Meeting. New Orleans, LA; Nov 15–18, 2018), they presented preliminary data from a phase III randomized trial with 500 plus patients, NRG CC001, supporting this concept.1 Patients with brain metastases were randomized to whole brain radiotherapy with or without hippocampal avoidance, and dosimetric compliance was monitored through rigorous central review. Patients on both arms also received memantine, based on results from a prior RTOG trial.

Between July 2016 and March 2018, the trial enrolled 518 adult patients with brain metastases who were stratified by RPA class and receipt of prior radiosurgery/surgery. The whole brain radiotherapy dose was 30 Gy in 10 fractions of 3 Gy each. The hippocampal maximum dose was to be kept below 15 Gy (and ideally <13.5 Gy), and the dose to 100% of the hippocampus was to be kept below 8.5 Gy (and ideally <7.5 Gy). Standardized neurocognitive function (NCF) tests were performed at baseline, 2, 4, 6, and 12 months. The primary endpoint was time to NCF failure, defined as decline on at least one of the following tests using the Reliable Change Index: Hopkins Verbal Learning Test-Revised, Trail Making Test, or Controlled Oral Word Association. Cumulative incidence was used to estimate time to NCF failure (death without NCF failure was treated as a competing risk) with between-arms differences tested using Gray’s test.

As expected, the trial primarily enrolled older patients with non–small cell lung cancer (almost 60%; fewer than 20% had breast cancer) with multiple brain metastases, with the vast majority (>85%) falling into RTOG RPA prognostic class II. The treatment arms did not differ in baseline clinical characteristics, baseline NCF, overall high-grade toxicity outcomes, overall survival, or intracranial progression. The time to NCF failure, the primary trial endpoint, was significantly longer in favor of hippocampal-avoidant whole brain radiotherapy with memantine (P=.012). The 6-month NCF failure rates were 69.1% (95% CI, 61.8–75.3) vs 58.0% (95% CI, 50.2–64.9) for whole brain radiotherapy with memantine vs hippocampal-avoidant whole brain radiotherapy with memantine, respectively. After adjusting for stratification variables, hippocampal-avoidant whole brain radiotherapy with memantine (HR, 0.73; 95%CI, 0.56–0.94; P=.016) and age ≤61 years (HR, 0.61; 95%CI, 0.46–0.81; P=.0006) remained robustly significant. Consequential to the cognitive protection engendered by hippocampal-avoidant whole brain radiotherapy with memantine, patient-reported symptom burden was also lower in this arm. The trial accrued at a rate of 16 patients per month and reached the accrual goal 2 years ahead of planned completion.

Several salient observations emerge from this trial:

  • Although there has been a significant increase in the utilization of stereotactic radiosurgery over whole brain radiotherapy over the last 3+ years because of the neurocognitive decline associated with whole brain radiotherapy, physicians and patients remain cognizant of the very high likelihood of intracranial relapse consequential to the use of radiosurgery alone, and therefore, NCF-preservation whole brain radiotherapy techniques, as employed in this trial, were met with enthusiastic support, completing enrollment 2 years ahead of schedule, a rather unusual circumstance in oncology trials.
  • The trial is an elegant demonstration of diligent bedside-to-bench-to-bedside research. The famous 1957 case of HM, who underwent bitemporal medial lobectomies for intractable seizures resulting in severe anterograde amnesia, provided the first genuine clinical clues about the role of the hippocampus in memory functions. Subsequent rodent work by several researchers, including, but not limited to that by Monje et al, established the presence of an exquisitely radiosensitive stem cell compartment in the peri-hippocampal location, which subserves a critical role in neurogenesis for memory formation. Prior work by Tome et al established the clinical significance, and dosimetric parameters for hippocampal sensitivity in humans, and NRG Oncology, in a series of trials, demonstrated that both chemical modulation (using memantine), and dosimetric preservation, using hippocampal-avoidant techniques, reduces rates of cognitive decline in patients receiving cranial radiotherapy.
  • Therefore, hippocampal avoidance for cranial malignancies well beyond brain metastases should now be considered whenever feasible. The contention here is logical; if the hippocampus of a patient with brain metastasis is sensitive to radiation, then the hippocampus of a patient with a low-grade glioma or another malignancy would also be radiation-sensitive; the underlying disease is not an excuse to not attempt hippocampal sparing. This now provides level I evidence for hippocampal sparing in patients with brain malignancies, thereby providing a fillip to technologies that can achieve this robustly, such as intensity-modulated photon and proton techniques.
  • Finally, the hazard ratio for cognitive preservation from hippocampal avoidance (in the presence of memantine) in this trial is 0.74; in the prior NRG Oncology trial RTOG 0614, the hazard ratio for cognitive preservation from the addition of memantine in patients receiving whole brain radiotherapy was 0.78. Therefore, the overall hazard ratio for hippocampal avoidance with memantine, in the context of patients receiving whole brain radiotherapy, is the product of the two hazard ratios, or 0.58, compared with whole brain radiotherapy. This is a very robust improvement, similar to, or even exceeding, that achieved in trials comparing radiosurgery with whole brain radiotherapy, thereby reigniting interest in trials of radiosurgery alone versus radiosurgery plus hippocampal-avoidant whole brain radiotherapy plus memantine, where one would expect similar cognitive outcomes but superiority in terms of intracranial disease control when whole brain radiotherapy is utilized. Such trials are already on the drawing board.

Management of Brain Metastases in Patients With Melanoma


Melanoma is the third most common systemic cancer that leads to brain metastases. The annual incidence of melanoma has increased over time, with brain metastases developing in 40% to 50% of patients with advanced melanoma. Traditional management of melanoma-related brain metastases has focused on symptom control as a result of the significant neurologic morbidity associated with the disease. Median overall survival for these patients, if untreated, is approximately 3 months. As with other brain metastases, a multidisciplinary treatment approach that includes surgery and radiation therapy is typically used, with historically little role for systemic, cytotoxic therapy. During the past decade, advancement within the field of genomics has led to the identification of melanoma-specific mutations, namely, v-Raf murine sarcoma viral oncogene homolog B and neuroblastoma RAS viral oncogene homolog, as well as to the development of agents that target these driver mutations. In addition, the advent of immunotherapies, specifically, agents that target cytotoxic T-lymphocyte antigen-4, anti–programmed death-1, and programmed death ligand-1, has increased the potential therapeutic options available to patients with both systemic and brain disease. With these advances, early trials have demonstrated improved overall survival in patients with brain metastases who receive these therapies either as single agents or as part of multimodality treatment regimens.

Impact of the radiosurgery prescription dose on the local control of small (2 cm or smaller) brain metastases



The impact of the stereotactic radiosurgery (SRS) prescription dose (PD) on local progression and radiation necrosis for small (≤ 2 cm) brain metastases was evaluated.


An institutional review board–approved retrospective review was performed on 896 patients with brain metastases ≤ 2 cm (3034 tumors) who were treated with 1229 SRS procedures between 2000 and 2012. Local progression and/or radiation necrosis were the primary end points. Each tumor was followed from the date of radiosurgery until one of the end points was reached or the last MRI follow-up. Various criteria were used to differentiate tumor progression and radiation necrosis, including the evaluation of serial MRIs, cerebral blood volume on perfusion MR, FDG-PET scans, and, in some cases, surgical pathology. The median radiographic follow-up per lesion was 6.2 months.


The median patient age was 56 years, and 56% of the patients were female. The most common primary pathology was non–small cell lung cancer (44%), followed by breast cancer (19%), renal cell carcinoma (14%), melanoma (11%), and small cell lung cancer (5%). The median tumor volume and median largest diameter were 0.16 cm3 and 0.8 cm, respectively. In total, 1018 lesions (34%) were larger than 1 cm in maximum diameter. The PD for 2410 tumors (80%) was 24 Gy, for 408 tumors (13%) it was 19 to 23 Gy, and for 216 tumors (7%) it was 15 to 18 Gy. In total, 87 patients (10%) had local progression of 104 tumors (3%), and 148 patients (17%) had at least radiographic evidence of radiation necrosis involving 199 tumors (7%; 4% were symptomatic). Univariate and multivariate analyses were performed for local progression and radiation necrosis. For local progression, tumors less than 1 cm (subhazard ratio [SHR] 2.32; p < 0.001), PD of 24 Gy (SHR 1.84; p = 0.01), and additional whole-brain radiation therapy (SHR 2.53; p = 0.001) were independently associated with better outcome. For the development of radiographic radiation necrosis, independent prognostic factors included size greater than 1 cm (SHR 2.13; p < 0.001), location in the corpus callosum (SHR 5.72; p < 0.001), and uncommon pathologies (SHR 1.65; p = 0.05). Size (SHR 4.78; p < 0.001) and location (SHR 7.62; p < 0.001)—but not uncommon pathologies—were independent prognostic factors for the subgroup with symptomatic radiation necrosis.


A PD of 24 Gy results in significantly better local control of metastases measuring < 2 cm than lower doses. In addition, tumor size is an independent prognostic factor for both local progression and radiation necrosis. Some tumor pathologies and locations may also contribute to an increased risk of radiation necrosis.

WBRT benefits for melanoma patients with brain metastases: Status of a clinical trial .f

What impact does whole-brain radiotherapy (WBRT) have on patients following surgery or stereotactic radiosurgery (SRS) for brain metastases? This has been a controversial question for years. A randomized stage III clinical trial launched in December 2008 expects to provide an answer. But when? What is its status, more than 6 years later? Recruitment to the WBRT in melanoma (WBRTMel) clinical trial reached its halfway goal with the 100th patient enrollment in December 2012, according to an article published May 8 in BMC Research Notes.

Principal investigator Professor Gerald B. Fogarty, MBBS, PhD, of the Melanoma Institute Australia and director of Mater Sydney Radiation Oncology in Sydney, reports that participation according to protocol is being followed and data acquisition is being appropriately acquired. Metastatic melanoma in the brain is a short-term death sentence. The quality of a patient’s remaining months is usually poor.

Whether WBRT following surgery or SRS is beneficial or harmful is, as yet, scientifically unproven. Researchers from multiple cancer treatment centers in Australia and New Zealand – members of the Australian and New Zealand Melanoma Trials Group (ANZMTG) and the Trans-Tasman Radiation Oncology Group (TROG) designed an international, multicenter, open-label, stratified 2-arm randomized phase III trial. Its objective is to assess the value of treating brain metastases in patients with AJCC (American Joint Committee on Cancer) stage IV melanoma using adjuvant postoperative WBRT with the hope of improving disease control and quality of life while maintaining satisfactory cognitive performance.

The rationale of WBRT is to treat microscopic disease at the site of initial metastasis and elsewhere in the brain to maintain long-term cerebral control. The primary objective is to assess using MRI the effect of WBRT on distant intercranial control – specifically a new metastasis developing within the brain 1 cm or more from a previous metastasis. The secondary objective of the trial is to assess the effect of WBRT on time to intracranial failure, quality of life, performance status, neurocognitive function, overall survival, and death from neurological causes. The researchers from the participating centers, which also include two hospitals in Oslo, Norway, hope to prove the hypothesis that patients treated with WBRT will show a 20% reduction in the rate of distant cranial metastases after at least 12 months of follow up compared to the patient cohort having “observation only.”

Randomization is being stratified by the number of cerebral metastases, the presence or absence of extracranial disease, patient age, sex, the radiotherapy dose, and the treatment center. The WBRT prescription is at least 30 Gy in 10 fractions commenced within 8 weeks of surgery and/or SRS. The first 100 patients are between 26 and 83 years old, 70% are male, and 59% were diagnosed with 1 brain metastasis, with 29% having 2 and 12% having 3. Almost half (47%) reached the primary endpoint. Thirteen percent experienced both local and distant failure by 12 months; the remaining 34% experienced distant failure only. The composition of each category with respect to whether the patients have received WBRT or not remains blinded. As of May 15, there are 169 patients in the trial, with 31 patients needed to close recruitment.

“WBRTMel is accruing well. Data quality is high and the final publication will shed light on the true impact of WBRT and hippocampal avoiding WBRT compared with observation,” said Dr. Fogarty. “Unfortunately, accrual is being slowed by the recent 2014 ASTRO Choosing Wisely recommendation to withhold WBRT after local treatment of brain metastases. The WBRTMel trial may show that this recommendation was made too soon.” One year following the final recruit, data will be analyzed. Proponents believe the results will update and define the benefit of WBRT. Critics say it will confirm that WBRT not only has no survival benefit because melanoma is radio-resistant, but adds the risk of causing neurocognitive problems. Whatever the findings, melanoma patients with brain metastases will benefit from this knowledge.

If You Are a Cancer Survivor, This Is a Must Read .

Getting through cancer treatment successfully is something to celebrate. To stay in good health, doctors say you need to watch for other symptoms, including vision changes, headaches and problems with balance.

What many cancer survivors don’t realize is that 25 percent of people who survive some common cancers go on to develop a brain tumor. These brain tumors don’t originate in the brain but are actually cancerous cells from the original tumor that travel to the brain through the bloodstream. When this happens, doctors call these tumors brain metastases.

“About one-third of patients with the most common cancers — lung, breast and kidney cancer and melanoma — are at risk of developing brain metastases,” says Cleveland Clinic neurosurgeon Gene Barnett, MD.

When this happens, the resulting growth needs early treatment. Dr. Barnett says early detection can help people get the right treatment at the right time to avoid serious complications. This is why you need to be vigilant and pay attention to your symptoms.

Watch for these 9 signs

If you’ve had cancer and experience these symptoms, be sure to tell your doctor:

  1. Vision changes (such as double vision or partial vision loss)
  2. Headaches (possibly with nausea)
  3. Numbness or tingling in part of the body
  4. Paralysis or difficulty moving any part of the body
  5. Inability to walk
  6. Difficulty with balance and an increased incidence of falls
  7. Difficulty speaking (including slurred words or incoherent speech)
  8. Problems with mental acuity (such as not being able to read or tell time)
  9. Seizure or convulsions

Metastatic brain tumors tend to develop gradually, although severe episodes can occur. No matter what, it’s important to tell your doctor immediately so he or she can evaluate you and treat you early as needed.

Treatable brain tumors

For years, doctors believed that brain metastases were uniformly fatal. Treatment could only to relieve symptoms. Today, they know that such tumors are treatable, thanks to technological and medical advances. The key is early detection.

To help in this fight, Cleveland Clinic teamed with the Northern Ohio American Cancer Society to establish the B-Aware Program. “Our goal is to educate at-risk cancer patients so that brain metastases are detected as early as possible, when they have the greatest number of treatment options,” says Dr. Barnett.

Many treatments available

We’ve come a long way from the days when the only treatment option available for brain metastases was whole brain radiation. This often failed to control the tumors. Today, aggressive and precisely delivered treatments produce better outcomes with fewer side effects.

Treatment options depend on the location, type and extent of the tumor, and include:

  • Radiosurgery. Radiosurgery directs highly focused beams of radiation at the tumor with extreme precision. This will not destroy the tumor, but may succeed in stopping tumor growth. Surgeons deliver this radiation so precisely that they can spare the surrounding brain tissue. Gamma Knife surgery is a common form of radiosurgery.
  • Minimal access surgery. This type of surgery allows doctors to remove the tumor in a faster, simpler way. Surgeons make a very small incision in the skull or hidden in a nearby structure. This reduces postoperative complications, minimizes pain and scarring, and shortens recovery time.
  • Localized radiotherapy, or radiation therapy. Radiotherapy exposes the cancerous cells to ionizing radiation that injures or destroys them. Doctors often use radiotherapy before or in addition to radiosurgery.
  • Medical therapies. Chemotherapy uses drugs to kill tumor cells that are dividing most rapidly. Many drugs used successfully for tumors in the body cannot penetrate into the brain. However, in certain cases, chemotherapy or other medical treatments may secure control of certain brain metastases.

“We want to help patients ‘be aware’ of all management options, so they don’t blindly agree to a proposed treatment which may not be in their best interest,” says Dr. Barnett. “They always have the right to seek a second opinion.”