Commentary (Pollock): Radiation Therapy in the Management of Brain Metastases From Renal Cell Carcinoma

May 1, 2006

Brain metastases from renal cell carcinoma (RCC) cause significant morbidity and mortality. More effective treatment approaches are needed. Traditionally, whole-brain radiotherapy has been used for palliation. With advances in radiation oncology, stereotactic radiosurgery and hypofractionated stereotactic radiotherapy have been utilized for RCC brain metastases, producing excellent outcomes. This review details the role of radiotherapy in various subgroups of patients with RCC brain metastases as well as the associated toxicities and outcomes. Newer radiosensitizers (eg, motexafin gadolinium [Xcytrin]) and chemotherapeutic agents (eg, temozolomide [Temodar]) used in combination with radiotherapy will also be discussed.

For some time, the standard of care for patients with metastatic brain disease was whole-brain radiation therapy (WBRT). Despite advances in the detection and treatment of brain metastases, the median survival for patients treated with WBRT alone is approximately 4 to 6 months, and tumor recurrence/progression is common if the patient survives more than 1 year. Nonetheless, it has been recognized that particular subsets of brain metastasis patients will benefit from a more aggressive approach. The most commonly utilized system is the Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) system.[1] As outlined by Doh and colleagues in their thorough review on the management of patients with brain metastases from renal cell carcinoma, survival appears to be longer for well selected patients when a more aggressive approach is employed, including surgical resection, stereotactic radiosurgery, or a combination of both techniques.

Role of the Neurosurgeon

The understanding that aggressive intervention is appropriate for many brain metastasis patients has markedly changed the role of neurosurgeons in the management of these patients.[2] Previously, neurosurgeons were typically consulted in one of three situations: First, in patients with presumed metastatic brain disease from an unknown primary site, a biopsy of an intracranial lesion (either stereotactically performed or excisional) was requested. Second, patients with a new diagnosis of metastatic brain disease and one or more large tumors causing symptomatic mass effect might require a neurosurgical consult. In such cases, it was realized that tumor resection was required to improve neurologic deficits and enable a patient to undergo WBRT. Third, following WBRT, if one or more tumors continued to progress and the patient was systemically stable, he or she was referred for consideration of tumor resection.

By these criteria, neurosurgeons were consulted about few patients in this setting. However, with studies showing improved survival times for patients with single metastases undergoing surgical resection in addition to WBRT-as well as the introduction of radiosurgery-the number of brain metastasis patients undergoing neurosurgical care continues to grow exponentially. This is significant if one considers that the total number of gliomas, meningiomas, schwannomas, and pituitary adenomas diagnosed each year in the United States is approximately 40,000, whereas the number of newly diagnosed brain metastasis patients is in the hundreds of thousands.

 

Treatment Decisions

The decision to recommend surgical resection or radiosurgery for brain metastasis patients is multifactorial. Patients with large tumors and symptomatic mass effect are poor candidates for radiosurgery. For such patients, surgical resection augmented by stereotactic guidance and awake cortical mapping (if the tumor is located in regions of the brain involved with speech and language) is indicated. In some patients with several large tumors, multiple craniotomies are performed in a single setting. The average length of hospital stay is 3 days. To minimize the chance of local tumor recurrence, we typically recommend postoperative WBRT once the patient has recovered from surgery. Another situation that favors surgical resection over radiosurgery is the patient with diabetes mellitus. Tumor removal generally permits the rapid elimination of corticosteroids, which makes blood glucose control much simpler.

Radiosurgery is generally preferred for patients with multiple tumors and for patients with tumors that cannot be safely resected with acceptable risk. Questions that remain unanswered relate to the appropriate roles of WBRT and radiosurgery[3] and the relative indications of surgical resection vs radiosurgery for patients with brain metastases.[4-6]

 

WBRT With or Without Radiosurgery

Kondziolka et al performed a randomized controlled trial in 27 patients to compare survival and tumor control using WBRT or WBRT and radiosurgery.[7] They found that combined WBRT and stereotactic radiosurgery significantly improved local tumor control for patients with two to four brain metastases compared to patients receiving WBRT alone. No difference was noted in patient survival, although a difference was detected between patients who underwent WBRT alone and those who later had salvage stereotactic radiosurgery or those who had initial WBRT and stereotactic radiosurgery.

Andrews et al recently reported a prospective randomized RTOG trial (RTOG 95-08) of WBRT vs WBRT plus radiosurgery for patients with one to three brain metastases.[8] WBRT plus radiosurgery provided a survival advantage compared to WBRT alone in the following patient groups: (1) patients with a single brain metastasis, (2) patients with two or three metastases and RPA class I, (3) patients with two or three metastases who were under the age of 50 years, (4) patients with two or three metastases and non-small-cell lung cancer or any squamous carcinoma. All subsets of patients in the WBRT-plus-stereotactic radiosurgery group were more likely to have a stable or improved performance status, improved local control, and reduced steroid dependence compared to the WBRT-alone group. Systemic disease remained the primary cause of death in both groups.

Consequently, these two studies provide level I evidence that radiosurgery improves local tumor control and is associated with better survival rates insubsets of patients with brain metastases.

 

Surgical Resection vs Radiosurgery

Three retrospective studies have compared the results of surgical resection to radiosurgery for patients with a single brain metastasis.[4-6] Bindal et al compared 13 patients undergoing radiosurgery to a matched group of 62 patients having surgical resection.[4] The median survival for the radiosurgery patients was 7.5 months, compared to 16.4 months in the microsurgical group. The difference in survival was attributed to progression of the treated tumor in the radiosurgical group-not systemic progression or the development of new metastatic disease in the brain.

Muacevic et al compared 52 patients undergoing microsurgery plus WBRT to 56 patients having only radiosurgery.[5] No difference was noted in survival, local tumor control, or neurologic death rates at 1 year after treatment. Perioperative morbidity and mortality were similar. O’Neill et al compared 74 patients undergoing microsurgery to 23 patients having radiosurgery.[6] No difference was noted in 1-year survival; local control was significantly better for the radiosurgery patients.

Unfortunately, the biases in these retrospective studies are substantial, and it is difficult to draw any firm conclusions regarding the best treatment for this heterogeneous patient population.

 

Conclusions

Although the prognosis for the majority of patients with brain metastases remains grim, early and aggressive intervention provides many patients with not only longer survival times, but also improved quality of life. Individualization of care is critical when deciding whether to proceed with tumor resection, stereotactic radiosurgery, or a combination of these techniques.

 

-Bruce E. Pollock, MD

Disclosures:

The author has no significant financial interest or other relationship with the manufacturers of any products.

References:

1. Gaspar L, Scott C, Rotman M, et al: Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastasis trials. Int J Radiat Oncol Biol Phys 37:745-751, 1997.

2. Pollock BE, Brown PD, Foote RL, et al: Properly selected patients with multiple brain metastases may benefit from aggressive treatment of their intracranial disease. J Neuro-Oncol 61:73-80, 2003.

3. Sneed PK, Lamborn KR, Forstner JM, et al: Radiosurgery for brain metastases: Is whole brain radiotherapy necessary? Int J Radiat Oncol Biol Phys 43:549-558, 1999.

4. Blindal AK, Blindal RK, Hess KR, et al: Surgery versus radiosurgery in the treatment of brain metastasis. J Neurosurg 84:748-754, 1996.

5. MuacevicA, Kreth FW, Horstmann GA, et al: Surgery and radiotherapy compared to gamma knife radiosurgery in the treatment of solitary cerebral metastases of small diameter. J Neurosurg 91:35-43, 1999.

6. O’Neill BP, Iturria NJ, Link MJ, et al: A comparison of surgical resection and stereotactic radiosurgery in the treatment of solitary brain metastases. Int J Radiat Oncol Biol Phys 55:1169-1176, 2003.

7. Kondziolka D, Patel A, Lunsford LD, et al: Stereotactic radiosurgery plus whole brain radiotherapy versus radiotherapy alone for patients with multiple brain metastases. Int J Radiat Oncol Biol Phys 45:427-434, 1999.

8. Andrews DW, Scott CB, Sperduto PW, et al: 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. Lancet 363:1665-1672, 2004.