Faculty Bibliography

OBJECTIVE: We define magnetic resonance imaging (MRI) and clinical criteria that differentiate radiation effect (RE) from tumor progression after stereotactic radiosurgery (SRS). METHODS: We correlated postoperative imaging and histopathological data in 68 patients who underwent delayed resection of a brain metastasis after SRS. Surgical resection was required in these patients because of clinical and imaging evidence of lesion progression 0.3 to 27.7 months after SRS. At the time of SRS, the median target volume was 7.1 mL (range, 0.5-26 mL), which increased to 14 mL (range, 1.3-81 mL) at the time of surgery. After initial SRS, routine contrast-enhanced MRI was used to assess tumor response and to detect potential adverse radiation effects. We retrospectively correlated these serial MRIs with the postoperative histopathology to determine if any routine MRI features might differentiate tumor progression from RE. RESULTS: The median time from SRS to surgical resection was 6.9 months (range, 0.3-27.7 months). A shorter interval from SRS to resection was associated with a higher rate of tumor recurrence (P = .014). A correspondence between the contrast-enhanced volume on T1-weighted images and the low signal-defined lesion margin on T2-weighted images ("T1/T2 match") was associated with tumor progression at histopathology (P < .0001). Lack of a clear and defined lesion margin on T2-weighted images compared to the margin of contrast uptake on T1-weighted images ("T1/T2 mismatch") was significantly associated with a higher rate of RE in pathological specimens (P < .0001). The sensitivity of the T1/T2 mismatch in identifying RE was 83.3%, and the specificity was 91.1%. CONCLUSIONS: We found that time to progression and T1/T2 mismatch were able to differentiate tumor progression from RE in most patients. When REs are suspected, surgery may not be necessary if patients respond to conservative measures. When tumor progression is suspected, resection or repeat radiosurgery can be effective, depending on the degree of mass effect.

PURPOSE: To evaluate the outcome of repeat stereotactic radiosurgery (SRS) for acoustic neuromas, we assessed tumor control, clinical outcomes, and the risk of adverse radiation effects in patients whose tumors progressed after initial management. METHODS AND MATERIALS: During a 21-year experience at our center, 1,352 patients underwent SRS as management for their acoustic neuromas. We retrospectively identified 6 patients who underwent SRS twice for the same tumor. The median patient age was 47 years (range, 35-71 years). All patients had imaging evidence of tumor progression despite initial SRS. One patient also had incomplete surgical resection after initial SRS. All patients were deaf at the time of the second SRS. The median radiosurgery target volume at the time of the initial SRS was 0.5 cc and was 2.1 cc at the time of the second SRS. The median margin dose at the time of the initial SRS was 13 Gy and was 11 Gy at the time of the second SRS. The median interval between initial SRS and repeat SRS was 63 months (range, 25-169 months). RESULTS: At a median follow-up of 29 months after the second SRS (range, 13-71 months), tumor control or regression was achieved in all 6 patients. No patient developed symptomatic adverse radiation effects or new neurological symptoms after the second SRS. CONCLUSIONS: With this limited experience, we found that repeat SRS for a persistently enlarging acoustic neuroma can be performed safely and effectively.

PURPOSE: To determine the indication and outcomes for Gamma Knife stereotactic radiosurgery (GKSRS) in the care of patients with intracranial sarcomatous metastases. METHODS AND MATERIALS: Data from 21 patients who underwent radiosurgery for 60 sarcomatous intracranial metastases (54 parenchymal and 6 dural-based) were studied. Nine patients had radiosurgery for solitary tumors and 12 for multiple tumors. The primary pathology was metastatic leiomyosarcoma (4 patients), osteosarcoma (3 patients), soft-tissue sarcoma (5 patients), chondrosarcoma (2 patients), alveolar soft part sarcoma (2 patients), and rhabdomyosarcoma, Ewing's sarcoma, liposarcoma, neurofibrosarcoma, and synovial sarcoma (1 patient each). Twenty patients received multimodality management for their primary tumor, and 1 patient had no evidence of systemic disease. The mean tumor volume was 6.2 cm(3) (range, 0.07-40.9 cm(3)), and a median margin dose of 16 Gy was administered. Three patients had progressive intracranial disease despite fractionated whole-brain radiotherapy before SRS. RESULTS: A local tumor control rate of 88% was achieved (including patients receiving boost, up-front, and salvage SRS). New remote brain metastases developed in 7 patients (33%). The median survival after diagnosis of intracranial metastasis was 16 months, and the 1-year survival rate was 61%. CONCLUSIONS: Gamma Knife radiosurgery was a well-tolerated and initially effective therapy in the management of patients with sarcomatous intracranial metastases. However, many patients, including those who also received fractionated whole-brain radiotherapy, developed progressive new brain disease.

Intracranial metastatic prostate carcinoma is rare. We sought to determine the clinical outcomes after Gamma Knife stereotactic radiosurgery (GKSRS) for patients with intracranial prostate carcinoma metastases. We studied data from 10 patients who underwent radiosurgery for 15 intracranial metastases (9 dural-based and 6 parenchymal). Six patients had radiosurgery for solitary tumors and four had multiple tumors. The primary pathology was adenocarcinoma (eight patients) and small cell carcinoma (two patients). All patients received multimodality management for their primary tumor (including resection, radiation therapy, androgen deprivation therapy) and eight patients had evidence of systemic disease at time of radiosurgery. The mean tumor volume was 7.7 cm(3) (range 1.1-17.2 cm(3)) and a median margin dose of 16 Gy was administered. Two patients had progressive intracranial disease in spite of fractionated partial brain radiation therapy (PBRT) prior to SRS. A local tumor control rate of 85% was achieved (including patients receiving boost, upfront and salvage SRS). New remote brain metastases developed in three patients (33%) and one patient had repeat SRS for tumor recurrence. The median survival after radiosurgery was 13 months and the 1-year survival rate was 60%. SRS was a well tolerated and effective therapy either alone or as a boost to fractionated radiation therapy in the management of patients with intracranial prostate carcinoma metastases.

TARGET POPULATION: This recommendation applies to adults with newly diagnosed brain metastases; however, the recommendation below does not apply to the exquisitely chemosensitive tumors, such as germinomas metastatic to the brain. RECOMMENDATION: Should patients with brain metastases receive chemotherapy in addition to whole brain radiotherapy (WBRT)? Level 1 Routine use of chemotherapy following WBRT for brain metastases has not been shown to increase survival and is not recommended. Four class I studies examined the role of carboplatin, chloroethylnitrosoureas, tegafur and temozolomide, and all resulted in no survival benefit. Two caveats are provided in order to allow the treating physician to individualize decision-making: First, the majority of the data are limited to non small cell lung (NSCLC) and breast cancer; therefore, in other tumor histologies, the possibility of clinical benefit cannot be absolutely ruled out. Second, the addition of chemotherapy to WBRT improved response rates in some, but not all trials; response rate was not the primary endpoint in most of these trials and end-point assessment was non-centralized, non-blinded, and post-hoc. Enrollment in chemotherapy-related clinical trials is encouraged.

QUESTION: What evidence is available regarding the use of whole brain radiation therapy (WBRT), stereotactic radiosurgery (SRS), surgical resection or chemotherapy for the treatment of recurrent/progressive brain metastases? TARGET POPULATION: This recommendation applies to adults with recurrent/progressive brain metastases who have previously been treated with WBRT, surgical resection and/or radiosurgery. Recurrent/progressive brain metastases are defined as metastases that recur/progress anywhere in the brain (original and/or non-original sites) after initial therapy. RECOMMENDATION: Level 3 Since there is insufficient evidence to make definitive treatment recommendations in patients with recurrent/progressive brain metastases, treatment should be individualized based on a patient's functional status, extent of disease, volume/number of metastases, recurrence or progression at original versus non-original site, previous treatment and type of primary cancer, and enrollment in clinical trials is encouraged. In this context, the following can be recommended depending on a patient's specific condition: no further treatment (supportive care), re-irradiation (either WBRT and/or SRS), surgical excision or, to a lesser extent, chemotherapy. Question If WBRT is used in the setting of recurrent/progressive brain metastases, what impact does tumor histopathology have on treatment outcomes? No studies were identified that met the eligibility criteria for this question.

QUESTION: Should patients with newly-diagnosed metastatic brain tumors undergo stereotactic radiosurgery (SRS) compared with other treatment modalities? Target population These recommendations apply to adults with newly diagnosed solid brain metastases amenable to SRS; lesions amenable to SRS are typically defined as measuring less than 3 cm in maximum diameter and producing minimal (less than 1 cm of midline shift) mass effect. Recommendations SRS plus WBRT vs. WBRT alone Level 1 Single-dose SRS along with WBRT leads to significantly longer patient survival compared with WBRT alone for patients with single metastatic brain tumors who have a KPS > or = 70.Level 1 Single-dose SRS along with WBRT is superior in terms of local tumor control and maintaining functional status when compared to WBRT alone for patients with 1-4 metastatic brain tumors who have a KPS > or =70.Level 2 Single-dose SRS along with WBRT may lead to significantly longer patient survival than WBRT alone for patients with 2-3 metastatic brain tumors.Level 3 There is class III evidence demonstrating that single-dose SRS along with WBRT is superior to WBRT alone for improving patient survival for patients with single or multiple brain metastases and a KPS<70 [corrected].Level 4 There is class III evidence demonstrating that single-dose SRS along with WBRT is superior to WBRT alone for improving patient survival for patients with single or multiple brain metastases and a KPS < 70. SRS plus WBRT vs. SRS alone Level 2 Single-dose SRS alone may provide an equivalent survival advantage for patients with brain metastases compared with WBRT + single-dose SRS. There is conflicting class I and II evidence regarding the risk of both local and distant recurrence when SRS is used in isolation, and class I evidence demonstrates a lower risk of distant recurrence with WBRT; thus, regular careful surveillance is warranted for patients treated with SRS alone in order to provide early identification of local and distant recurrences so that salvage therapy can be initiated at the soonest possible time. Surgical Resection plus WBRT vs. SRS +/- WBRT Level 2 Surgical resection plus WBRT, vs. SRS plus WBRT, both represent effective treatment strategies, resulting in relatively equal survival rates. SRS has not been assessed from an evidence-based standpoint for larger lesions (>3 cm) or for those causing significant mass effect (>1 cm midline shift). Level 3: Underpowered class I evidence along with the preponderance of conflicting class II evidence suggests that SRS alone may provide equivalent functional and survival outcomes compared with resection + WBRT for patients with single brain metastases, so long as ready detection of distant site failure and salvage SRS are possible. SRS alone vs. WBRT alone Level 3 While both single-dose SRS and WBRT are effective for treating patients with brain metastases, single-dose SRS alone appears to be superior to WBRT alone for patients with up to three metastatic brain tumors in terms of patient survival advantage.

QUESTION: Should patients with newly-diagnosed metastatic brain tumors undergo open surgical resection versus whole brain radiation therapy (WBRT) and/or other treatment modalities such as radiosurgery, and in what clinical settings? TARGET POPULATION: These recommendations apply to adults with a newly diagnosed single brain metastasis amenable to surgical resection. RECOMMENDATIONS: Surgical resection plus WBRT versus surgical resection alone Level 1 Surgical resection followed by WBRT represents a superior treatment modality, in terms of improving tumor control at the original site of the metastasis and in the brain overall, when compared to surgical resection alone. Surgical resection plus WBRT versus SRS + or - WBRT Level 2 Surgical resection plus WBRT, versus stereotactic radiosurgery (SRS) plus WBRT, both represent effective treatment strategies, resulting in relatively equal survival rates. SRS has not been assessed from an evidence-based standpoint for larger lesions (>3 cm) or for those causing significant mass effect (>1 cm midline shift). Level 3 Underpowered class I evidence along with the preponderance of conflicting class II evidence suggests that SRS alone may provide equivalent functional and survival outcomes compared with resection + WBRT for patients with single brain metastases, so long as ready detection of distant site failure and salvage SRS are possible. Note The following question is fully addressed in the WBRT guideline paper within this series by Gaspar et al. Given that the recommendation resulting from the systematic review of the literature on this topic is also highly relevant to the discussion of the role of surgical resection in the management of brain metastases, this recommendation has been included below.