Mark E. Linskey

The role of whole brain radiation therapy in the management of newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline

AbstractShould whole brain radiation therapy (WBRT) be used as the sole therapy in patients with newly-diagnosed, surgically accessible, single brain metastases, compared with WBRT plus surgical resection, and in what clinical settings?Target population This recommendation applies to adults with newly diagnosed single brain metastases amenable to surgical resection; however, the recommendation does not apply to relatively radiosensitive tumors histologies (i.e., small cell lung cancer, leukemia, lymphoma, germ cell tumors and multiple myeloma). RecommendationSurgical resection plus WBRT versus WBRT aloneLevel 1 Class I evidence supports the use of surgical resection plus post-operative WBRT, as compared to WBRT alone, in patients with good performance status (functionally independent and spending less than 50% of time in bed) and limited extra-cranial disease. There is insufficient evidence to make a recommendation for patients with poor performance scores, advanced systemic disease, or multiple brain metastases. If WBRT is used, is there an optimal dosing/fractionation schedule?Target population This recommendation applies to adults with newly diagnosed brain metastases. RecommendationLevel 1 Class I evidence suggests that altered dose/fractionation schedules of WBRT do not result in significant differences in median survival, local control or neurocognitive outcomes when compared with “standard” WBRT dose/fractionation. (i.e., 30 Gy in 10 fractions or a biologically effective dose (BED) of 39 Gy10). If WBRT is used, what impact does tumor histopathology have on treatment outcomes?Target population This recommendation applies to adults with newly diagnosed brain metastases. Recommendation Given the extremely limited data available, there is insufficient evidence to support the choice of any particular dose/fractionation regimen based on histopathology.The following question is fully addressed in the surgery guideline paper within this series by Kalkanis 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 WBRT in the management of brain metastases, this recommendation has been included below. Does the addition of WBRT after surgical resection improve outcomes when compared with surgical resection alone?Target population This recommendation applies to adults with newly diagnosed single brain metastases amenable to surgical resection. RecommendationSurgical resection plus WBRT versus surgical resection aloneLevel 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.

Gamma knife radiosurgery for acoustic tumors: multivariate analysis of four year results

In order to evaluate the results of radiosurgery for acoustic tumors and to identify optimum treatment parameters, an analysis of tumor control, as well as incidences of hearing loss, facial and trigeminal neuropathies was undertaken. Between August 1987 and August 1991, 134 patients with 136 acoustic tumors received stereotactic gamma knife radiosurgery at the University of Pittsburgh. Median follow-up was 24 months (range: 6-56 months). Tumor volumes ranged from 0.10 to 17.00 cm3 (median = 2.75 cm3). From one to ten isocenters were utilized per tumor treated (median = 3). Minimum tumor doses varied from 12 to 20 Gy (median = 17 Gy). The 4-year actuarial tumor control rate was 89.2 +/- 6.0%. Some degree of hearing (by pure tone audiometry) was preserved in 71.0 +/- 4.4% of patients. The actuarial rates for preservation of either pretreatment hearing level or useful hearing were 34.4 +/- 6.6% and 35.1 +/- 97% respectively. Respectively, the actuarial incidences of postradiosurgery facial and trigeminal neuropathies were 29.0 +/- 4.4% and 32.9 +/- 4.5%, respectively. No significant factors affecting tumor control were identified. Multivariate analysis identified a significantly increased risk of hearing loss in patients with neurofibromatosis (p = 0.0003) as well as decreased risks of facial and trigeminal neuropathies with both decreasing tumor diameter (p = 0.001) and increasing number of isocenters treated (p = 0.003). Radiosurgery is a safe and effective treatment for acoustic neuromas with acceptable morbidity that may be lowered by the use of multiple isocenter treatment techniques and by earlier treatment of small tumors.

Cranial nerve length predicts the risk of delayed facial and trigeminal neuropathies after acoustic tumor stereotactic radiosurgery

PURPOSE To test the hypothesis that length of cranial nerve irradiated is a major factor predicting the risk of cranial nerve injury following radiosurgery and to identify any other significant related treatment factors. METHODS AND MATERIALS Ninety-two patients (93 acoustic tumors) were treated with a 201 source Cobalt-60 gamma unit from 1987 to 1990 and prospectively followed. The range of minimum tumor dose was 12-20 Gy and maximum dose 24-50 Gy. Univariate and multivariate analyses were used to evaluate any correlations between tumor measurements and treatment factors, with the development of trigeminal and facial neuropathies following radiosurgery. RESULTS The risks of trigeminal and facial neuropathy following radiosurgery were associated with the pon-petrous distance and mid porous transverse tumor diameters respectively (anatomically related to the irradiated length of cranial nerves V and VII respectively) in both univariate (p = .002 for V and p = .026 for VII) and multivariate (p = .004 for V and p = .055 for VII) analyses. Tumor volume, other tumor measurements, maximum dose, minimum tumor dose, and tumor dose inhomogeneity were not significantly related to either trigeminal or facial neuropathy in univariate and multivariate analyses. CONCLUSION Within a minimum tumor dose range of 12-20 Gy, the incidence of delayed trigeminal or facial neuropathy depended more on the estimated length of nerve irradiated than the tumor dose or tumor volume. In the future, the risk of delayed facial or trigeminal cranial neuropathy may be reduced significantly by performing radiosurgery when the tumor still has both a small mid-porous transverse diameter and a small pons-petrous distance.

Aneurysms of the Intracavernous Carotid Artery: Natural History and Indications for Treatment

Of 37 patients with 44 intracavernous carotid artery aneurysms (ICCAAns) diagnosed between 1976 and 1988, patients with 20 aneurysms were followed without treatment for 5 months to 13 years (median, 2.4 years). Ten of the 20 ICCAAns were asymptomatic at diagnosis, and 10 were symptomatic. Three of the asymptomatic ICCAAns were symptomatic at follow-up. One of these required clipping because of a progressing cavernous sinus syndrome; the other 2 were minimally symptomatic and have not required treatment. Of the 10 initially symptomatic ICCAAns, 2 had not changed, 4 became more symptomatic, and 4 had symptomatically improved by follow-up. One patient with an ICCAAn that had not changed clinically was lost to follow-up 6 months after diagnosis. Of the 4 ICCAAns that became more symptomatic, 2 continue to be monitored, and 2 required intervention: one with detachable balloon occlusion of the aneurysm with preservation of the internal carotid artery lumen, and the other with gradual cervical internal carotid artery occlusion. The clinical course of this selected group of patients with ICCAAns suggests that the natural history of ICCAAns can be quite variable. Although clinical progression does occur, symptomatic ICCAAns also can improve spontaneously. Therapeutic intervention for asymptomatic ICCAAns should be reserved for patients with aneurysms arising at the anterior genu of the carotid siphon and/or extending into the subarachnoid space, where subarachnoid hemorrhage is most likely. Intervention for symptomatic ICCAAns should be reserved for patients with subarachnoid hemorrhage, epistaxis, severe facial or orbital pain, evidence of radiographic enlargement, progressive ophthalmoplegia, or progressive visual loss.

Response assessment criteria for brain metastases: proposal from the RANO group

CNS metastases are the most common cause of malignant brain tumours in adults. Historically, patients with brain metastases have been excluded from most clinical trials, but their inclusion is now becoming more common. The medical literature is difficult to interpret because of substantial variation in the response and progression criteria used across clinical trials. The Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) working group is an international, multidisciplinary effort to develop standard response and progression criteria for use in clinical trials of treatment for brain metastases. Previous efforts have focused on aspects of trial design, such as patient population, variations in existing response and progression criteria, and challenges when incorporating neurological, neuro-cognitive, and quality-of-life endpoints into trials of patients with brain metastases. Here, we present our recommendations for standard response and progression criteria for the assessment of brain metastases in clinical trials. The proposed criteria will hopefully facilitate the development of novel approaches to this difficult problem by providing more uniformity in the assessment of CNS metastases across trials.

Radiosurgery of acoustic neurinomas.

Eighty‐five patients with acoustic neurinomas underwent stereotactic radiosurgery with the gamma unit at the University of Pittsburgh (Pittsburgh, PA) during its first 30 months of operation. Neuroimaging studies performed in 40 patients with more than 1 year follow‐up showed that tumors were smaller in 22 (55%), unchanged in 17 (43%), and larger in one (2%). The 2‐year actuarial rates for preservation of useful hearing and any hearing were 46% and 62%, respectively. Previously undetected neuropathies of the trigeminal (n = 12) and facial nerves (n = 14) occurred 1 week to 1 year after radiosurgery (median, 7 and 6 months, respectively), and improved at median intervals of 13 and 8 months, respectively, after onset. Hearing loss was significantly associated with increasing average tumor diameter (P = 0.04). No deterioration of any cranial nerve function has yet developed in seven patients with average tumor diameters less than 10 mm. Radiosurgery is an important treatment alternative for selected acoustic neurinoma patients.

The role of chemotherapy in the management of newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline.

Target populationThis 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.RecommendationShould 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.

Radiosurgery for acoustic neurinomas : early experience

We reviewed our early experience with the first 26 patients with acoustic neurinomas (21 unilateral, 5 bilateral) treated by stereotactic radiosurgery using the first North American 201-source cobalt-60 gamma knife. Follow-up ranged from 6 to 19 months (median, 13 months). Serial postoperative imaging showed either a decrease in tumor size (11 patients) or growth arrest (15 patients). Loss of central contrast enhancement was a characteristic change (18 patients). Seven patients had good or serviceable hearing preoperatively. In all 7 the preoperative hearing status was retained immediately after radiosurgery. At follow-up, 3 had preserved hearing, 1 had reduced hearing, and 3 had lost all hearing in the treated ear. Hearing in 1 patient that was nonserviceable preoperatively later improved to a serviceable hearing level. Delayed facial paresis developed in 6 patients, and delayed trigeminal sensory loss developed in 7 patients, none of whom had significant deficits before radiosurgery. Both facial and trigeminal deficits tended to improve within 3 to 6 months of onset with excellent recovery anticipated. Lower cranial nerve dysfunction was not observed. All 26 patients remain at their preoperative employment or functional status. At present, stereotactic radiosurgery is an alternative treatment for acoustic neurinomas in patients who are elderly, have significant concomitant medical problems, have a tumor in their only hearing ear, have bilateral acoustic neurinomas, refuse microsurgical excision, or have recurrent tumor despite surgical resection. Although longer and more extensive follow-up is required, the control of tumor growth and the acceptable rate of complications in this early experience testifies to the future expanding role of this technique in the management of selected acoustic neurinomas.

The role of retreatment in the management of recurrent/progressive brain metastases: a systematic review and evidence-based clinical practice guideline

AbstractQuestionWhat 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. RecommendationLevel 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. QuestionIf 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.

Tumor Control after Stereotactic Radiosurgery in Neurofibromatosis Patients with Bilateral Acoustic Tumors

During a 4-year interval, 17 patients with bilateral acoustic tumors (vestibular schwannomas) underwent unilateral stereotactic radiosurgery using a multisource gamma unit; 2 patients underwent radiosurgery of both tumors in separate sessions. Eleven patients with unoperated contralateral tumors served as concurrent controls to compare the effects of radiosurgery with the natural history of acoustic tumors. After radiosurgery, the tumor control and regression rates were 89.5 and 21.1%, respectively (median neuroimaging follow-up, 1.4 years; range, 0.3-3.9). The tumor regression rate increased to 40% for patients evaluated at least 12 months after radiosurgery. In comparison to the unoperated contralateral tumors, stereotactic radiosurgery achieved tumor control, as assessed by the ultimate change in tumor size at follow-up (P, 0.012), the change in tumor size over time (P, 0.006), and tumor growth rates (P, 0.003). This study provided convincing evidence that tumor stabilization after radiosurgery (as assessed by neuroimaging) truly represented tumor control. The incidence of delayed facial neuropathy after radiosurgery compared favorably with the incidence reported after microsurgical removal. Some hearing was preserved in one-third of the patients who had preoperative hearing, including three patients who were contralaterally deaf. Stereotactic radiosurgery should be considered as a primary surgical modality for many patients with neurofibromatosis Type II.