QuestionShould patients with newly-diagnosed metastatic brain tumors undergo stereotactic radiosurgery (SRS) compared with other treatment modalities?Target populationThese 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.RecommendationsSRS plus WBRT vs. WBRT aloneLevel 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 ≥ 70.Level 2 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 ≥ 70.Level 3 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 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 aloneLevel 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 ± WBRTLevel 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 aloneLevel 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.

QuestionShould 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 populationThese recommendations apply to adults with a newly diagnosed single brain metastasis amenable to surgical resection.RecommendationsSurgical 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.Surgical resection plus WBRT versus SRS ± WBRTLevel 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.QuestionDoes surgical resection in addition to WBRT improve outcomes when compared with WBRT alone?Target populationThis recommendation applies to adults with a newly diagnosed single brain metastasis 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.

Endoscopic transsphenoidal pituitary surgery has become increasingly more popular for the removal of pituitary adenomas. It is also widely recognised that transsphenoidal microscopic removal of pituitary adenomas is a well-established procedure with good outcomes. Our objective was to meta-analyse the short-term results of endoscopic and microscopic pituitary adenoma surgery. We undertook a systematic review of the English literature on results of transsphenoidal surgery, both microscopic and endoscopic from 1990 to 2011. Series with less than 10 patients were excluded. Pooled data were analysed using meta-analysis techniques to obtain estimate of death, complication rates and extent of tumour removal. Complications evaluated included cerebrospinal fluid leak, meningitis, vascular complications, visual complications, diabetes insipidus, hypopituitarism and cranial nerve injury. Data were also analysed for tumour size and sex. 38 studies met the inclusion criteria yielding 24 endoscopic and 22 microscopic datasets (eight studies included both endoscopic and microscopic series). Meta-analysis of the available literature showed that the endoscopic transsphenoidal technique was associated with a higher incidence of vascular complications (p<0.0001). No difference was found between the two techniques in all other variables examined. Meta-analysis of the available literature reveals that endoscopic removal of pituitary adenoma, in the short term, does not seem to confer any advantages over the microscopic technique and the incidence of reported vascular complications was higher with endoscopic than with microscopic removal of pituitary adenomas. While we recognise the limitations of meta-analysis, our study suggests that a multicentre, randomised, comparative effectiveness study of the microscopic and endoscopic transsphenoidal techniques may be a reasonable approach towards establishing a true valuation of these techniques.

QuestionDo steroids improve neurologic symptoms in patients with metastatic brain tumors compared to no treatment? If steroids are given, what dose should be used? Comparisons include: (1) steroid therapy versus none. (2) comparison of different doses of steroid therapy.Target populationThese recommendations apply to adults diagnosed with brain metastases.RecommendationsSteroid therapy versus no steroid therapyAsymptomatic brain metastases patients without mass effectInsufficient evidence exists to make a treatment recommendation for this clinical scenario.Brain metastases patients with mild symptoms related to mass effectLevel 3 Corticosteroids are recommended to provide temporary symptomatic relief of symptoms related to increased intracranial pressure and edema secondary to brain metastases. It is recommended for patients who are symptomatic from metastatic disease to the brain that a starting dose of 4–8 mg/day of dexamethasone be considered.Brain metastases patients with moderate to severe symptoms related to mass effectLevel 3 Corticosteroids are recommended to provide temporary symptomatic relief of symptoms related to increased intracranial pressure and edema secondary to brain metastases. If patients exhibit severe symptoms consistent with increased intracranial pressure, it is recommended that higher doses such as 16 mg/day or more be considered.Choice of SteroidLevel 3 If corticosteroids are given, dexamethasone is the best drug choice given the available evidence.Duration of Corticosteroid AdministrationLevel 3 Corticosteroids, if given, should be tapered slowly over a 2 week time period, or longer in symptomatic patients, based upon an individualized treatment regimen and a full understanding of the long-term sequelae of corticosteroid therapy.Given the very limited number of studies (two) which met the eligibility criteria for the systematic review, these are the only recommendations that can be offered based on this methodology. Please see “Discussion” and “Summary” section for additional details.

Influence of surgical trauma on experimental metastasis in healing wounds is investigated using a transplantable murine mammary carcinoma cell line, TA3Ha. Intravenous injection of 10(5), 10(6), and 2 x 10(6) TA3Ha cells into syngeneic Strain A mice led to liver or kidney tumor development in none of the 96, ten, and ten mice tested, respectively. In contrast, injection of 10(5) cells into mice immediately after hepatic wedge resection performed using milliwatt carbon dioxide laser and electrocautery resulted in tumor formation at the site of trauma in 21/37 (57%) and 25/52 (48%) mice, (P less than 0.001) respectively. Similar results were obtained in mice subjected to partial nephrectomy using the laser (nine of 18) and electrocautery (eight of 13). These results clearly demonstrate that surgical trauma renders a nonprivileged organ susceptible to experimental metastasis formation, and that at least in this model both laser and electrocautery have similar effects. Tumor cell injection 1, 7, and 10 days posthepatic surgery resulted in 36%, 20%, and 0% tumor formation, respectively, indicating that the earlier events in wound healing support tumor implantation and/or growth better than those later on. Frequency of tumor formation at sites of trauma in the peritoneum induced by scalpel blade, laser, and electrocautery were 28%, 50% and 82%, respectively. Peritoneal tumors were seen in 33% of the nonsurgical mice. Skin incisions induced with the three above probes had little influence on experimental metastasis formation. Thus the influence of trauma on tumor formation is not uniform in every organ.

Should 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 populationThis 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 populationThis 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 populationThis recommendation applies to adults with newly diagnosed brain metastases.RecommendationGiven 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 populationThis 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.

Twenty-four patients with petroclival meningiomas were operated upon at the neurosurgical clinic of the City Hospital of Hannover between 1978 and 1987. Seventeen were women and seven men; the mean age was 45 years. Symptoms were usually present for more than 2 years before the diagnosis was made. The most common symptom was disturbance of gait; the most common preoperative sign was cranial nerve deficit, mainly of the 7th and 8th nerves. Preoperative neuroradiological evaluation included computed tomography and four-vessel cerebral angiography. Fifteen patients (62%) had a tumor larger than 2.5 cm in its major diameter. The surgical approaches used were the retromastoid, pterional, subtemporal, and combined retromastoid-subtemporal. We developed a modification of the retromastoid-subtemporal approach with preservation of the transverse sinus and used this in the last 2 patients. There was no postoperative death; 11 patients (46%) suffered postoperative complications, mainly in the form of cranial nerve deficits, often reversible. "Total" tumor removal was achieved in 17 patients (71%). Twenty patients (83%) were independent at the time of discharge from the hospital. With accurate neuroradiological evaluation, careful choice of the surgical approach, and sound application of microsurgical techniques, petroclival meningiomas may be "totally" and safely resected in a significant number of patients.

Thirty-one patients operated upon for supratentorial glioblastomas or anaplastic astrocytomas were studied to evaluate the effect of the extent of surgical resection on the length and quality of survival. The median age was 50 years and the median preoperative Karnofsky rate was 80. Twenty-one patients (68%) had glioblastoma multiforme, and 10 patients (32%) had anaplastic astrocytoma. Early postoperative enhanced computed tomography was used to determine the extent of tumor resection. Gross total tumor resection was accomplished in 19 patients (61%), and subtotal resection was performed in 12 patients (39%). The two groups were comparable regarding age, sex, pathological condition, preoperative Karnofsky rating, tumor location, postoperative radiation therapy, and postoperative chemotherapy (P greater than 0.05). The gross total resection group lived longer than the subtotal resection group by life table analysis (P less than 0.001; median survival of 90 and 43 weeks, respectively). Postoperatively, the mean functional ability measured by the Karnofsky rating was significantly increased in the gross total resection group (P = 0.006), but not in the subtotal resection group (P greater than 0.05). The difference in degree of change between preoperative and postoperative Karnofsky rating in the two groups was statistically significant (P = 0.002). The gross total resection group spent significantly more time after the operation in an independent status (Karnofsky rating greater than or equal to 80) compared to the subtotal resection group (P = 0.007; median time of 185 and 12.5 weeks, respectively). Gross total resection of supratentorial glioblastomas and anaplastic astrocytomas is feasible and is directly associated with longer and better survival when compared to subtotal resection.