Multimodality treatment of melanoma brain metastases incorporating stereotactic radiosurgery (SRS)

Wolfram E. Samlowski, Cancer 2007;109:1855

Brain metastases are a frequent complication in advanced melanoma. A 3.6 to 4.1-month median survival has been reported after treatment with whole brain radiotherapy. We performed a retrospective analysis of our institutional experience of multimodality treatment utilizing linear accelerator (Linac)-based stereotactic radiosurgery (SRS). Forty-four melanoma patients with brain metastases underwent 66 SRS treatments for 156 metastatic foci between 1999 and 2004. Patients were treated with initial SRS if 5 brain metastases were present. All patients had Karnofsky Performance Status (KPS) 70, but 37 patients had active systemic metastases (Recursive Partition Analysis Class 2). Dose was prescribed to the isodose line, which covered 95% of the target volume (range, 74%-96%). Conformity indices were calculated for each lesion. Dose was based on maximal diameter of the metastasis as follows: <2 cm, 22 Gy; 2-3 cm, 18 Gy; 3 cm, 15 Gy. Lesions >4 cm were usually not considered for SRS, although rare exceptions were made.


RESULTS.The median survival of melanoma patients with brain metastases was 11.1 months  from diagnosis. One-year and 2-year survivals were 47.7% and 17.7%, respectively. There was no apparent effect of age or sex. Surgery or multiple stereotactic radiotherapy treatments were associated with prolonged survival. Addition of WBRT to maintain control of brain metastases in a subset of patients did not improve survival.
CONCLUSIONS.Our results suggest that aggressive treatment of patients with up to 5 melanoma brain metastases including SRS appears to prolong survival. Subsequent chemotherapy or immunotherapy after SRS may have contributed to the observed outcome.

Annually, an estimated 97,000-170,000 cancer patients in the US develop brain metastases. Melanoma ranks 4th overall as a cause of brain metastases (10% of patients with brain metastases), after lung and breast cancer, and unknown primary tumors, but is 2nd highest in incidence proportion percentage. Approximately 10% to 13% of patients presenting with regional disease (AJCC stage III) are at risk for brain metastases, and 18% to 46% of stage IV patients will develop central nervous system (CNS) involvement, with a prevalence of 55% to 75% at autopsy.  Factors that may associate with development of brain metastases include male gender, mucosal or head and neck primaries, as well as deep or ulcerated lesions. Development of brain metastases leads directly to the patient's death in the majority of cases.  Current management strategies appear unsatisfactory,  and melanoma patients with brain metastases are usually excluded from participation in clinical trials due to a general perception of an adverse prognosis.

Surgical resection, usually followed by radiotherapy, has been employed to treat brain metastases in selected patients (usually with solitary, superficial lesions). Extended survival can be achieved in patients with high performance status or Radiation Therapy Oncology Group (RTOG) Recursive Partition Analysis (RPA) Class I (Karnofsky Performance Status [KPS] 70%, primary site controlled, <65 years old, and no evidence of systemic metastases outside the brain).  Because multiple, rather than solitary, brain metastases are believed to be more common in melanoma, the majority of patients with melanoma brain metastases are not considered surgical candidates. In unresectable patients, whole brain radiotherapy (WBRT, generally 3000 cGy in 10 fractions) has been widely employed to palliate brain metastases. In larger series, median survival of patients with melanoma brain metastases treated with WBRT has ranged from 3.6 to 4.8 months. Fife  recently published treatment results from 686 patients treated between 1985-2000 at the Sydney Melanoma Unit. These investigators found a median survival of 8.7 to 8.9 months in 205 patients treated with surgery with or without radiotherapy (generally for a solitary metastasis), whereas patients treated with WBRT (236 patients) had a median survival of 3.4 months and patients who received supportive care only (210 patients) had a median survival of only 2.1 months. These results underscore the need for improved treatment algorithms for melanoma patients with brain metastases.

A series of recent publications have suggested high local control rates for brain metastases with stereotactic radiosurgery (SRS), using either linear accelerator (Linac)- or Gamma-Knife-based approaches.  In these studies SRS has generally been limited to patients with 1 to 3 metastases, with rare series accepting patients with larger numbers of lesions.  We report our encouraging institutional experience, based on expanded eligibility for Linac-based SRS for patients with up to 5 brain metastases, followed by planned systemic therapy.

Patients with advanced melanoma develop brain metastases with such a high frequency that development of appropriate screening and management strategies represents an important clinical challenge. What appears extremely clear is that nontreatment of melanoma brain metastases (palliative care) results in rapid patient decline and death.  Surgical resection, usually followed by radiotherapy, has been employed to treat brain metastases in selected patients (generally solitary metastases in a superficial location).  These patients may have extended survival, particularly if they have a high performance status or RTOG RPA class I (KPS >70%, no synchronous systemic metastases).  Most patients with melanoma brain metastases are not considered surgical candidates. In these patients WBRT (generally 3000 cGy in 10 fractions) has been widely employed to palliate brain metastases, resulting in 3.6 to 4.8-month median survival.  Performance status and RTOG RPA class are important determinants of survival after WBRT.

We used SRS as the primary treatment for 44 sequential patients with melanoma brain metastases, using a multimodality treatment algorithm. Subsequent systemic therapy was also planned if metastatic disease was not limited to the CNS. In our series half of the patients presented with a solitary brain metastasis. The other half had multiple metastases. Our results indicate that the vast majority of patients with brain metastases from melanoma can be effectively treated using SRS as the mainstay of therapy. SRS demonstrated a high local control rate, with median duration of response in treated lesions lasting 10.2 months and a prolonged median survival (11.1 months  from diagnosis). We found that additional SRS treatments, surgical resection, and WBRT could be employed as an adjunct to initial SRS treatment to maintain control of brain metastases. Exploratory Cox univariate analysis suggested that surgery and multiple SRS treatments appeared to correlate with prolonged survival. Furthermore, 81% of patients with concurrent non-CNS metastases tolerated subsequent systemic treatment without undue toxicity. Although not quantified, quality of life and neurologic function appeared well maintained for protracted periods.

The SRS treatment approach was based on recent publications suggesting high local control rates for brain metastases treated with SRS using either Linac- or Gamma-Knife-based approaches.  In a melanoma-specific patient series, Gonzales-Martinez  treated 24 patients with 115 lesions with Gamma-Knife (mean radiotherapy dose 16.4 Gy), with a median survival of 5.5 months after radiosurgery. Median tumor volume treated was 4 cm3. Noel treated 25 patients with 61 melanoma brain metastases using invasive immobilization and Linac-based radiosurgery (mostly for 1-3 metastases). The median dose was 17 Gy and local control was achieved in 81% at 1 year. Median survival was 8 months, with 29% 1-year survival. Herfarth  employed Linac stereotactic radiotherapy in 64 patients with 122 melanoma brain metastases, with a median dose of 20 Gy. CNS control was achieved in 81% and median survival was 10.6 months. Radbill treated 188 melanoma brain metastases in 51 patients using a Gamma-Knife, achieving 81% local control in the CNS. A 17.7-month survival was achieved in patients with a solitary metastasis, compared with 4.6 months for patients with multiple metastases. RPA class I patients had a median survival of 57 weeks vs 20 weeks for RPA class II or III. The majority of patients had additional brain metastases develop. Selek reported the results of Linac-based SRS in 103 patients with 153 brain metastases. The median tumor volume treated was 1.8 cm3, with a median tumor dose of 18 Gy. Local control of treated lesion was 49% and CNS progression-free survival was 15% at 1 year. Overall survival was 25% at 1 year. Koc  treated 26 melanoma patients with 72 brain metastases using Gamma-Knife. The median survival was 9 months from diagnosis and 1 year survival was 25%.  Recently, Gaudy-Marqueste  updated results of Gamma-Knife treatment of 1 to 4 melanoma brain metastases. These investigators treated 221 brain metastases in 106 patients (61.3% were solitary metastases). A high local control rate (83.7) was observed, but median survival was found to be only 5.1 months. A number of conclusions can be drawn from these studies, in conjunction with our own data: SRS or Gamma-Knife treatment appears to produce high control rates in patients with small numbers of brain metastases and good performance status. Some of these studies, including our own, also demonstrated prolonged progression-free and overall survival. In contrast to some published series, single brain metastases and use of additional WBRT did not confer survival benefit.

Because all surviving patients in the current series were followed for a minimum of 1 year after SRS, we can clearly define causes of treatment failure. Six (14%) patients currently remain alive in remission or continue to respond to therapy (only 1 of these initially presented with a CNS-only recurrence, the rest had systemic metastatic disease). Of the 38 patients who died, 6 (14%) died of systemic progression only, 11 (25%) died with concurrent systemic and CNS, and 21 (48%) patients died predominantly of CNS progression. These results indicate that, whereas SRS provides lengthy palliation, maintenance of quality of life and prolongation of survival, further improvement in CNS control is needed, as progression at treated sites and development of new brain metastases contributed to eventual death in 73% of patients.

Whether SRS treatment can be used without routine addition of WBRT is currently being evaluated. In a series of renal cancer, melanoma and sarcoma patients treated for 1 to 3 brain metastases using radiosurgery by the Eastern Cooperative Oncology Group, intracranial failure rates were 25.8% and 48.3% at 3 and 6 months, respectively. Failure rates within and outside the treatment volume appeared similar. This translated into a median survival of 8.3 months. It is difficult to analyze the impact of SRS in melanoma patients, however, because this was not separately reported. Still, those authors concluded that the intracranial failure rate suggested that routine avoidance of WBRT should be approached judiciously. A recent randomized study by Aoyama demonstrated that addition of WBRT to SRS did not significantly improve survival in patients with 1 to 4 brain metastases (mostly lung cancer), with a median survival of 8.0 months with SRS alone, vs 7.5 months with SRS + WBRT. CNS recurrences were seen in 29 of 67 patients after SRS alone, compared with 10 of 65 patients treated with SRS + WBRT. This resulted in frequent addition of salvage WBRT in the SRS-only group. It is clear from our study and that of Aoyama et al that salvage therapy after SRS is feasible without adverse effects on overall survival. The advantage of this approach is avoidance of any unnecessary CNS toxicity from additional radiotherapy (SRS or WBRT) in approximately 50% of patients. The question of whether SRS alone is adequate initial treatment for patients with 5 brain metastases with delayed WBRT or SRS salvage vs SRS and immediate WBRT will require a randomized trial to resolve (ideally including neurocognitive and quality of life assessment). It should be noted that patients who require WBRT after failure of SRS for >5 new brain metastases may have less favorable disease, compared with those eligible for SRS retreatment with 5 metastases.

In conclusion, we report an encouraging institutional experience treating melanoma brain metastases, based on expanded eligibility for Linac-based SRS for patients with up to 5 brain metastases. Based on our results, we propose the following treatment algorithm. SRS treatment of melanoma brain metastases followed by systemic treatment provides appears to provide useful palliation and prolonged survival. Due to improvements in linear accelerator design and computerized treatment planning software, even more complex SRS treatment planning is currently possible. Based on the these results, exclusion of appropriately treated patients with melanoma brain metastases from clinical trials does not appear warranted because survival is similar to stage IV melanoma overall. There remains a need to develop more active agents for treatment of metastatic melanoma, with particular emphasis on drugs that penetrate into the CNS to reduce the high incidence of brain metastases.