Vol. 15, Issue 4 Jul 2015

Case Management: Treatment of Brain Metastases

Contributing Author: Kevin McMullen, MD

ACCREDITATION STATEMENT
Indiana University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

DESIGNATION STATEMENT
Indiana University School of Medicine designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

FACULTY DISCLOSURE STATEMENT
In accordance with the Accreditation Council for Continuing Medical Education (ACCME) Standards for Commercial Support, educational programs sponsored by Indiana University School of Medicine (IUSM) must demonstrate balance, independence, objectivity, and scientific rigor. All faculty, authors, editors, and planning committee members participating in an IUSM-sponsored activity are required to disclose any relevant financial interest or other relationship with the manufacturer(s) of any commercial product(s) and/or provider(s) of commercial services that are discussed in an educational activity.

COMMITTEE AND AUTHOR DISCLOSURE
Statements of Disclosure of Relevant Financial Relationships have been obtained from Kevin McMullen, MD. Dr. McMullen has disclosed that he has no relevant financial relationships with any commercial interests.

OBJECTIVES
After reading this article, the reader should be able to:

  • Discuss brain metastases with regard to incidence and associated primary malignancies.
  • Describe the use of systemic therapy for the treatment of de novo and recurrent brain metastases.
  • Identify the role of neurosurgical resection for new, recurrent, and multiple brain metastases.
  • Compare and contrast whole brain radiotherapy with stereotactic radiosurgery (SRS) for the management of brain metastases.
  • Summarize the expected outcomes from SRS in patients with brain metastases.

Date of original release: July 2015
Date of expiration: July 2016

Note: While it offers CME credits, this activity is not intended to provide extensive training or certification in the field.

Overview of Brain Metastases and Renal Cell Carcinoma

Brain metastases are the most common intracranial lesions in adults, accounting for more than half of all brain tumors and developing in 10 to 30 percent of adults with systemic malignancies.1 Moreover, the incidence of brain metastases may be increasing, owing to improved detection of small lesions by MRI and enhanced control of extracranial disease. In adults, the most common primary tumors responsible for brain metastasis are melanoma and lung, breast, colorectal, and renal cell carcinomas (Table 1).2,3 In contrast, non-melanoma skin cancers and carcinomas of the prostate, esophagus, and oropharynx rarely spread to the brain.

Renal cell cancer (RCC), which originates within the renal cortex, is responsible for 80 to 85 percent of all primary kidney neoplasms. In the United States, an estimated 62,000 new RCC cases will be diagnosed in 2015, and 14,000 people will die from this disease.4 According to the National Cancer Institute Surveillance, Epidemiology and End Results (SEER) registry, RCC is more common in men than women and predominantly occurs in the sixth to eighth decade of life, with the median age at diagnosis 64 years. Approximately 17 percent of patients with RCC present with metastases.

Case Study

In 2007, a 67-year-old woman is diagnosed with RCC that has spread to her maxillary sinus and gallbladder. She is treated with right nephrectomy, right maxillectomy with reconstruction, and gallbladder resection. In 2011, a distal pancreatectomy is performed, again for metastatic disease. No postoperative adjuvant therapy is given.

In February 2012, the patient is seen at IU Health for follow-up. Magnetic resonance imaging (MRI) shows two intracranial lesions—one located in the left temporal lobe with left intraventricular extension, the other a small nodule in the right cerebellar hemisphere. Both lesions are consistent with metastatic RCC.

Treatment of Brain Metastases

"In patients with more than one contrast-enhancing brain parenchymal lesion and a history of metastatic cancer, we generally assume that these lesions represent metastases, unless aspects of the clinical presentation raise suspicion of other etiologies, such as infection," says Kevin McMullen, MD, staff physician with IU Health Physicians Radiation Oncology and associate professor of clinical radiation oncology at Indiana University School of Medicine. "The principal aims of treatment for metastatic disease, regardless of its site, are to improve the duration and the quality of survival. Three options are available for the treatment of brain metastases: systemic therapy, surgery, and radiotherapy."

Systemic Therapy

Systemic therapy generally does not provide adequate treatment for brain metastases, even for those that are chemosensitive. Consequently, initial systemic therapy for newly diagnosed brain metastases is generally recommended only within the clinical trial setting.5

Salvage systemic therapy may be considered for patients with brain metastases who have a reasonable performance status. The drugs used should be capable of entering into the central nervous system (CNS) at effective concentrations.

One such drug is temozolomide, an alkylating agent approved for the treatment of high-grade gliomas. The use of this drug for metastatic cancer has primarily been limited to patients with melanoma metastases who have failed first- and secondline systemic therapy. However, temozolomide has also been shown to stabilize recurrent/progressive brain metastases, with a few patients experiencing complete responses,6 and is a model for development of newer CNS-active systemic agents. Systemic agents that do not cross the blood-brain barrier must have an extra-CNS effect that impacts intra-CNS tumors. Two drugs that may have this mechanism of action—bevacizumab, an antiangiogenic agent, and ipilimumab, an immune system modulator—are currently being evaluated for the treatment of brain metastases.

"The principal aims of treatment for metastatic disease, regardless of its site, are to improve the duration and the quality of survival. Three options are available for the treatment of brain metastases: systemic therapy, surgery, and radiotherapy."

Surgery

Surgery for brain metastases can ameliorate the intracranial mass effect, thus facilitating recovery from neurologic deficits. Surgery also reduces the need for long-term steroid therapy and provides tumor tissue for molecular subclassification, potentially guiding subsequent treatment. Among the patient and tumor factors that influence the effectiveness of neurosurgery for brain metastases are: 1) number of brain lesions, 2) surgical accessibility to the lesions, 3) likelihood of significant tumor invasiveness, 4) status of the systemic disease, and 5) radioresistance of the metastatic tumor.

Data support the use of resection for a solitary brain metastasis7 and for patients with multiple metastases with a dominant mass requiring surgical decompression. Advances in surgical techniques, such as microsurgical resection and intraoperative MRI, may be helpful in optimizing local tumor control. Owing to the high risk for recurrence following surgery alone, however, adjuvant whole brain radiotherapy (WBRT) is frequently administered postoperatively. Data from two prospective randomized trials found that patients with a single or limited number of brain metastases treated with surgical resection plus WBRT had fewer intracranial recurrences and were less likely to die of neurologic causes than those treated with surgery alone.8,9

The role of neurosurgical resection for multiple or recurrent brain metastases has not been rigorously evaluated, and no prospective randomized clinical trials are currently underway. Nonetheless, surgery alone or combined with WBRT may provide functional improvement in carefully selected patients.

Radiotherapy

Two types of radiotherapy are used for the treatment of brain metastases: WBRT and stereotactic radiosurgery (SRS).

Whole Brain Radiotherapy. WBRT has long been a cornerstone in the treatment of brain metastases, typically used in patients with four or more radiographically evident metastases10 or with lesions greater than 4 cm in size. The most frequently employed WBRT regimen for brain metastases uses 30 to 37.5 Gy administered in 2.5 to 3 Gy fractions.

The effectiveness of WBRT in improving CNS control notwithstanding, toxicity is a major concern. Fatigue (which can be life-altering for some patients), total scalp alopecia that may be permanent, radiation-induced endocrinopathy requiring hormone replacement therapy, dry eye, and cataracts are all well-recognized side effects of WBRT, according to Dr. McMullen. However, the most serious adverse event associated with treatment is the development of neurocognitive deficits.

"When these deficits develop, they are irreversible and worsen over time," Dr. McMullen cautions. "Large cooperative group studies have shown that whole brain avoidance, pretreatment with the neuroprotective NMDA receptor antagonist memantine, and use of a hippocampal-sparing technique when appropriate can limit the neurocognitive toxicity of WBRT."11-13

Stereotactic Radiosurgery. SRS uses multiple convergent gamma rays from a cobalt-60 source (Gamma Knife®) or X-rays from a modified linear accelerator (Linac®, CyberKnife®) to precisely deliver a single high dose of radiation to a brain metastasis with the intent of maximizing local control while sparing normal brain tissue. SRS is suitable for patients with limited cranial metastases and can be performed alone as initial therapy, as an adjuvant to surgical resection, or as a boost to WBRT.

"At IU Health, stereotactic radiosurgery is usually performed using the Perfexion Gamma Knife, which simultaneously focuses 192 cobalt pencil beams on a target lesion," Dr. McMullen describes. "Radiation delivery is painless, and the primary side effects are swelling and bleeding. Very rarely, infection may develop, associated with the placement of pins used with the stereotactic head frame. Radiation necrosis may develop up to two years after radiosurgery and can require short- or long-term treatment with corticosteroids. In unusual cases, patients may receive hyperbaric oxygen therapy or require surgery to remove the necrotic debris."

Case Study (cont.)

The patient chooses to undergo Gamma Knife SRS for the treatment of her brain metastases. On the day of the procedure, she is given a light sedative. Local anesthetic is applied to her head, and a titanium frame is securely placed around her head using four small pins. An MRI scan is obtained to delineate the exact location of the lesions in relation to surrounding brain structures (Figure 1). Treatment planning is done using the scan and 3-D computer software (Figure 2). Once the plan is finalized, the patient is positioned for treatment (Figure 3), and SRS is performed, with a total of 24 Gy delivered to each lesion. Following the 45-minute procedure, the head frame is removed, skin care is provided to the sites of pin attachment, and the patient is discharged to home.

An MRI is obtained 12 weeks post-SRS and every three months thereafter. During the first year, her scans show mild treatment-effect enlargement of the metastases before the left temporal lobe lesion resolves completely and the right cerebellar lesion decreases in size and stabilizes.

Outcomes following SRS are encouraging. A recently published meta-analysis examined pooled data from 364 patients with one to four brain metastases enrolled in three randomized controlled trials evaluating SRS with or without WBRT.14 The investigators found a survival advantage for patients ≤50 years who received SRS as initial therapy. While age did not increase the risk of local tumor failure, beyond age 50, the risk for new distant brain metastases was significantly greater in patients treated with SRS monotherapy. These patients are candidates for another course of SRS, WBRT, or surgery, depending on the location and size of the new lesion(s).

SRS may be a particularly good choice for the management of brain metastases from RCC, which are considered less responsive to fractionated WBRT. A retrospective analysis of 166 patients with RCC showed that the use of SRS to treat a limited number of brain lesions provided excellent local control and was an effective—if not preferred—treatment modality.15

"Unlike WBRT, stereotactic radiosurgery can be repeated if necessary, allowing brain metastases to be stabilized longterm and preserving neurocognitive function for brain tumor survivors," Dr. McMullen explains. "Radiosurgery does not yet have a major impact on overall survival because most patients with metastatic cancer die from progression of their primary tumor or extracranial metastases, not brain metastases. In the future, the excellent control of metastatic brain disease provided by SRS will work in concert with improving systemic therapy to provide longer survivals and excellent neurologic quality of life."

Case Study (cont.)

During a follow-up visit 26 months after SRS, the patient reports the recent onset of mild cognitive symptoms but an otherwise excellent quality of life. An MRI reveals two new brain lesions. After discussing all treatment options, a second SRS is scheduled.

SRS may be a particularly good choice for the management of brain metastases from RCC, which are considered less responsive to fractionated WBRT. A retrospective analysis of 166 patients with RCC showed that the use of SRS to treat a limited number of brain lesions provided excellent local control and was an effective—if not preferred—treatment modality.15

Kevin McMullen, MD

IU Health Physicians Radiation Oncology
Associate Professor of Clinical Radiation Oncology Indiana University School of Medicine
kmcmulle@iuhealth.org

Dr. McMullen is a graduate of the Mayo Medical School in Rochester, MN and received his residency training in radiation oncology at Wake Forest University School of Medicine in Winston-Salem, NC. His clinical interests include pediatric oncology, stereotactic radiotherapy/radiosurgery, central nervous system tumors, cancer of the reticuloendothelial system, skin cancer, palliative care, and quality of life/neurocognition.

Dr. McMullen is a member of the Society for Neuro-Oncology, Children's Oncology Group, American Society for Therapeutic Radiology/Oncology, and American Radium Society. The author or more than 55 peer-reviewed journal ar ticles and several textbook chapters, he teaches and lectures extensively in the United States and abroad.

Before coming to IU School of Medicine in 2011, Dr. McMullen served as a US Army brigade flight surgeon, stationed at Fort Hood, TX, and subsequently was appointed director of the radiation oncology residency program at Wake Forest University School of Medicine. He is the Indiana Lions Endowed Scholar in Cancer Survivorship.

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