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Background Quality-adjusted-life-years (QALYs) are used to concurrently quantify morbidity and mortality within a single parameter. For this reason, QALYs can facilitate the discussion of risks and benefits during patient counseling regarding treatment options. QALYs are often calculated using partitioned-survival modelling. Alternatively, QALYs can be calculated using more flexible and informative state-transition models populated with transition rates estimated using multistate modelling (MSM) techniques. Unfortunately the latter approach is considered not possible when only progression-free survival (PFS) and overall survival (OS) analyses are reported. Methods We have developed a method that can be used to estimate approximate transition rates from published PFS and OS analyses (we will refer to transition rates estimated using full multistate methods as true transition rates). Results The approximation method is more accurate for estimating the transition rates out of health than the transition rate out of illness. The method tends to under-estimate true transition rates as censoring increases. Conclusions In this article we present the basis for and use of the transition rate approximation method. We then apply the method to a case study and evaluate the method in a simulation study. Electronic supplementary material The online version of this article (10.1186/s12962-019-0182-7) contains supplementary material, which is available to authorized users.

Pretreatment evaluation is performed to determine the number, location, and size of the brain metastases and magnetic resonance imaging (MRI) is the recommended imaging technique, particularly in patients being considered for surgery or stereotactic radiosurgery. A contiguous thin-cut volumetric MRI with gadolinium with newer gadolinium-based agents can improve detection of small brain metastases. A systemic workup and medical evaluation are important, given that subsequent treatment for the brain metastases will also depend on the extent of the extracranial disease and on the age and performance status of the patient. Patients with hydrocephalus or impending brain herniation should be started on high doses of corticosteroids and evaluated for possible neurosurgical intervention. Patients with moderate symptoms should receive approximately 4-8 mg/d of dexamethasone in divided doses. The routine use of corticosteroids in patients without neurologic symptoms is not necessary. There is no proven benefit of anticonvulsants in patient without seizures. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

Multiple options for retreatment are available, which include whole-brain radiation therapy, stereotactic radiosurgery, surgery, chemotherapy, and supportive care. Size, number, timing, location, histology, performance status, and extracranial disease status all need to be carefully considered when choosing a treatment modality. There are no randomized trials examining the retreatment of brain metastases. Repeat whole-brain radiation has been examined in a single-institution experience, showing the potential for clinical responses in selected patients. Local control rates as high as 91% using stereotactic radiosurgery for relapses after whole-brain radiation are reported. Surgery can be indicated in progressive and/or hemorrhagic lesions causing mass effect. The role of chemotherapy in the recurrent setting is limited but some agents may have activity on the basis of experiences on a smaller scale. Supportive care continues to be an important option, especially in those with a poor prognosis. Follow-up for brain metastases patients is discussed, examining the modality, frequency of imaging, and imaging options in differentiating treatment effect from recurrence. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of the current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

Single brain metastasis represents a common neurologic complication of cancer. Given the number of treatment options that are available for patients with brain metastasis and the strong opinions that are associated with each option, appropriate treatment for these patients has become controversial. Prognostic factors such as recursive partitioning analysis and graded prognostic assessment can help guide treatment decisions. Surgery, whole brain radiation therapy (WBRT), stereotactic radiosurgery or combination of these treatments can be considered based on a number of factors. Despite Class I evidence suggestive of best therapy, the treatment recommendation is quite varied among physicians as demonstrated by the American College of Radiology's Appropriateness Panel on single brain metastasis. Given the potential concerns of the neurocognitive effects of WBRT, the use of SRS alone or SRS to a resection cavity has gained support. Since aggressive local therapy is beneficial for survival, local control and quality of life, the use of these various treatment modalities needs to be carefully investigated given the growing number of long-term survivors. Enrollment of patients onto clinical trials is important to advance our understanding of brain metastasis.

Do prophylactic anticonvulsants decrease the risk of seizure in patients with metastatic brain tumors compared with no treatment? Target population These recommendations apply to adults with solid brain metastases who have not experienced a seizure due to their metastatic brain disease. Recommendation Level 3 For adults with brain metastases who have not experienced a seizure due to their metastatic brain disease, routine prophylactic use of anticonvulsants is not recommended. Only a single underpowered randomized controlled trial (RCT), which did not detect a difference in seizure occurrence, provides evidence for decision-making purposes.

What evidence is available regarding the emerging and investigational therapies for the treatment of metastatic brain tumors? Target population These recommendations apply to adults with brain metastases. Recommendations New radiation sensitizers Level 2 A subgroup analysis of a large prospective randomized controlled trial (RCT) suggested a prolongation of time to neurological progression with the early use of motexafin-gadolinium (MGd). Nonetheless this was not borne out in the overall study population and therefore an unequivocal recommendation to use the currently available radiation sensitizers, motexafin-gadolinium and efaproxiral (RSR 13) cannot be provided. Interstitial modalities There is no evidence to support the routine use of new or existing interstitial radiation, interstitial chemotherapy and or other interstitial modalities outside of approved clinical trials. New chemotherapeutic agents Level 2 Treatment of melanoma brain metastases with whole brain radiation therapy and temozolomide is reasonable based on one class II study. Level 3 Depending on individual circumstances there may be patients who benefit from the use of temozolomide or fotemustine in the therapy of their brain metastases. Molecular targeted agents Level 3 The use of epidermal growth factor receptor inhibitors may be of use in the management of brain metastases from non-small cell lung carcinoma.

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). Recommendation Surgical resection plus WBRT versus WBRT alone Level 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. Recommendation Level 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. Recommendation 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.

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 ≥ 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 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.

To determine the efficacy of motexafin gadolinium (MGd) in combination with whole brain radiotherapy (WBRT) for the treatment of brain metastases from non-small-cell lung cancer.In an international, randomized, Phase III study, patients with brain metastases from non-small-cell lung cancer were randomized to WBRT with or without MGd. The primary endpoint was the interval to neurologic progression, determined by a centralized Events Review Committee who was unaware of the treatment the patients had received.Of 554 patients, 275 were randomized to WBRT and 279 to WBRT+MGd. Treatment with MGd was well tolerated, and 92% of the intended doses were administered. The most common MGd-related Grade 3+ adverse events included liver function abnormalities (5.5%), asthenia (4.0%), and hypertension (4%). MGd improved the interval to neurologic progression compared with WBRT alone (15 vs. 10 months; p = 0.12, hazard ratio [HR] = 0.78) and the interval to neurocognitive progression (p = 0.057, HR = 0.78). The WBRT patients required more salvage brain surgery or radiosurgery than did the WBRT+MGd patients (54 vs. 25 salvage procedures, p0.001). A statistically significant interaction between the geographic region and MGd treatment effect (which was in the prespecified analysis plan) and between treatment delay and MGd treatment effect was found. In North American patients, where treatment was more prompt, a statistically significant prolongation of the interval to neurologic progression, from 8.8 months for WBRT to 24.2 months for WBRT+MGd (p = 0.004, HR = 0.53), and the interval to neurocognitive progression (p = 0.06, HR = 0.73) were observed.In the intent-to-treat analysis, MGd exhibited a favorable trend in neurologic outcomes. MGd significantly prolonged the interval to neurologic progression in non-small-cell lung cancer patients with brain metastases receiving prompt WBRT. The toxicity was acceptable.

STUDY DESIGN Randomized clinical trial. OBJECTIVE.: To determine if age affects outcomes from differing treatments in patients with spinal metastases. SUMMARY OF BACKGROUND DATA Recently, class I data were published supporting surgery with radiation over radiation alone for patients with malignant epidural spinal cord compression (MESCC). However, the criteria to properly select candidates for surgery remains controversial and few independent variables which predict success after treatment have been identified. METHODS Data for this study was obtained in a randomized clinical trial comparing surgery versus radiation for MESCC. Hazard ratios were determined for the effect of age and the interaction between age and treatment. Age estimates at which prespecified relative risks could be expected were calculated with greater than 95% confidence to suggest possible age cut points for further stratification. Multivariate models and Kaplan-Meier curves were tested using stratified cohorts for both treatment groups in the randomized trial each divided into 2 age groups. RESULTS Secondary data analysis with age stratification demonstrated a strong interaction between age and treatment (hazard ratio = 1.61, P = 0.01), such that as age increases, the chances of surgery being equal to radiation alone increases. The best estimate for the age at which surgery is no longer superior to radiation alone was calculated to be between 60 and 70 years of age (95% CI), using sequential prespecified relative risk ratios. Multivariate modeling and Kaplan-Meier curves for stratified treatment groups showed that there was no difference in outcome between treatments for patients >or=65 years of age. Ambulation preservation was significantly prolonged in patients

Whole brain radiation therapy (WBRT) is the standard of care for most patients with greater than four brain metastases. WBRT in these patients has been shown to improve neurologic symptoms, decrease progression of intracranial disease, and lengthen survival. In patients with one to four brain metastases, the utility of focal therapies such as neurosurgery or stereotactic radiosurgery (SRS), as well as concern over the possible neurotoxicities of WBRT, has lead to questions regarding its use in this population. However, studies looking at combined regimens of focal treatment plus WBRT vs. WBRT alone have not been able to produce conclusive evidence of either increased neurotoxicity or improved survival with the use of WBRT due to issues of lack of power, significant crossover between the randomized groups, and inconsistent endpoints. Similarly, investigations into the neurocognitive functioning of patients being treated for brain metastases have not effectively taken into account confounding factors including baseline neurologic status, radiation dose and fractionation, the effects of other palliative and anti-cancer medications, and the definition of truly clinically relevant endpoints. Two findings that have been consistently shown in these trials are that progression of disease within the brain leads to a significant decline in neurocognitive functioning, and that WBRT significantly decreases recurrence of disease within the brain. Fortunately, studies looking at various fractionation schemes have shown that there is enough flexibility in the delivery of WBRT to accommodate the patient’s overall goals of therapy while somewhat mediating the risk of unwanted effects. Finally, it is important to understand that, the shortcomings of the current body of literature notwithstanding, the process of reconciling the benefits of WBRT with the risks must include a clear perspective regarding the fact that while the concerns surrounding this therapy remain unproven, the detrimental clinical consequences of omitting WBRT are clear.

Chemotherapy has a place in the treatment of several types of pineal region tumors. For gliomas, treatment is similar to gliomas elsewhere in the brain. True and germ cell tumors are chemosensitive and chemotherapy is sometimes useful at recurrence or in an adjuvant or neo-adjuvant setting. For non-germinomatous germ cell tumors, adjuvant chemotherapy is often used. For pineal parenchymal tumors, chemotherapy may be useful at recurrence. However, most of the information on efficacy of various chemotherapeutic agents comes from clinical series rather than randomized trials. The use of chemotherapy is evolving in tumors of the pineal area.

Purpose: A recent randomized clinical trial has demonstrated that direct decompressive surgery plus radiotherapy was superior to radiotherapy alone for the treatment of metastatic epidural spinal cord compression. The current study compared the cost-effectiveness of the two approaches. Methods and Materials: In the original clinical trial, clinical effectiveness was measured by ambulation and survival time until death. In this study, an incremental cost-effectiveness analysis was performed from a societal perspective. Costs related to treatment and posttreatment care were estimated and extended to the lifetime of the cohort. Weibull regression was applied to extrapolate outcomes in the presence of censored clinical effectiveness data. Results: From a societal perspective, the baseline incremental cost-effectiveness ratio (ICER) was found to be $60 per additional day of ambulation (all costs in 2003 Canadian dollars). Using probabilistic sensitivity analysis, 50% of all generated ICERs were lower than $57, and 95% were lower than $242 per additional day of ambulation. This analysis had a 95% CI of $72.74 to 309.44, meaning that this intervention ranged from a financial savings of $72.74 to a cost of $309.44 per additional day of ambulation. Using survival as the measure of effectiveness resulted in an ICER of $30,940 per life-year gained. Conclusions: We found strong evidence that treatment of metastatic epidural spinal cord compression with surgery in addition to radiotherapy is cost-effective both in terms of cost per additional day of ambulation, and cost per life-year gained. © 2006 Elsevier Inc. Metastatic spinal cord compression, Cost-effectiveness, Clinical trials, Radiotherapy, Surgery, Secondary neoplasm.

PURPOSE Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) prognostic classes I and II for patients with brain metastases is derived from a database made up primarily of patients with unresected and multiple metastases. An analysis of a previously published randomized trial was performed to determine the applicability of these RPA prognostic classes in the setting of resection of single metastases to the brain. PATIENTS AND METHODS Ninety-five patients with single metastases to the brain that were treated with complete surgical resection entered this study. Patients were randomly assigned to treatment with postoperative whole brain radiotherapy (WBRT) (n = 49 patients) or no further brain treatment (n = 46 patients). All patients entered on this study had a Karnofsky performance status of > or =70. Therefore, although the RTOG RPA has 3 classes, only patients with RPA classes I (n = 26) or II (n = 69) were eligible for this study analysis. RESULTS For RPA class I, the median survival was 10.9 months versus 9.8 months for class II patients (P = 0.45). Multivariate analysis showed that only postoperative WBRT, independent of RPA class I or II, lessened the risk of brain tumor recurrence (P < 0.0001). CONCLUSION This analysis of a randomized trial evaluating postoperative WBRT in the treatment of single metastases to the brain showed no difference in survival between RPA class I or II patients. In addition, the use of postoperative WBRT after complete surgical resection of single brain metastases results in substantially better control of disease in the brain independent of RPA classes I or II.

Purpose The national standard stereostatic radiosurgery (SRS) dose for brain metastases ≤2 cm is 24 Gy as established by the Radiation Therapy Oncology Group study 90–05, in which planned whole brain radiotherapy (WBRT) was not used. On the basis of our institutional experience, the goal of this study was to determine the optimal SRS dose and influence of WBRT on local tumor control among 468 ≤2-cm metastases. Methods and materials Between October 1992 and May 2001, 468 newly diagnosed or recurrent ≤2-cm brain metastases, among 160 patients, were treated with SRS (dose range, 7–30 Gy; median, 20). A total of 240 metastases received planned WBRT (range, 6.75–50.4 Gy; median, 40.5) vs. 228 metastases that did not. The variables tested by multivariate analysis for their potential effect on tumor control included histologic type, site of metastasis, primary diagnosis, tumor volume, SRS dose, newly diagnosed vs. recurrent metastasis, and planned WBRT vs. no planned WBRT. Results Follow-up ranged from 1 to 82 months (median 7). On multivariate analysis, the addition of WBRT was the most significant predictor of local tumor control. Overall, patients who received WBRT had superior local tumor control rates (97% vs. 87% in those who did not receive WBRT; p = 0.0001). Patients receiving WBRT and SRS ≥20 Gy achieved local control rates of 99% compared with 91% control rates when treated with WBRT and SRS p = 0.0029). Increasing the SRS dose to >20 Gy resulted in no improvement in local tumor control and a higher rate of Grade 3 and 4 neurotoxicity, approaching statistical significance (5.9% vs. 1.9%, p = 0.078). Conclusion First, optimal control of brain metastasis ≤2 cm was seen with 20-Gy SRS combined with planned WBRT. Second, SRS doses >20 Gy resulted in no obvious improvement in local control and appeared to be associated with a greater rate of complications.

Purpose A multi-institutional trial was conducted by the Radiation Therapy Oncology Group (RTOG) to test the feasibility of performing a test battery consisting of five neurocognitive measures and a quality-of-life instrument in patients with brain metastases. Methods and materials The major eligibility requirements included histologic proof of a primary malignancy, measurable single or multiple brain metastases, Zubrod performance status of 0–1, neurologic function status of 0–2, and “certification” for administration of neurocognitive assessments. This certification process required either attendance at an RTOG neurocognitive assessment training workshop or review of an instructional video, followed by submission of an audiotape of mock/simulated test sessions for central review. The test battery included the following measures: the Mini-Mental Status Examination, Hopkins Verbal Learning Test, Verbal Fluency/Controlled Word Association Test, Ruff 2 and 7 test, Trailmaking Test, and Profile of Mood States-Short Form. The primary objective of this trial was to establish whether patients were able to complete this test battery. Compliance was defined as successful completion of a test measure. The test battery was to be administered just before, at completion of, and 1 month after whole brain radiotherapy to 37.5 Gy at 2.5 Gy/fraction once daily. Fifty-nine patients were enrolled in the trial. Results The patient characteristics included 32% ≥65 years; 44% with Zubrod performance status of 0; and 81% with multiple brain metastases. The overall compliance rate for administration and completion of the five neurocognitive measures and a quality-of-life instrument before treatment, at treatment completion, and 1 month after treatment was ≥95%, ≥84%, and ≥70%. The most common causes of noncompliance were patient-related factors (e.g., performance status or inability to understand test instructions) and not institutional error. Conclusion Neurocognitive evaluation of patients with brain metastases in a multi-institutional and cooperative group setting is feasible using the test battery and certification process used in this study. This battery and certification process will be incorporated into future RTOG brain tumor trials.

Brain metastases are neoplasms that originate in tissues outside the brain and then spread secondarily to the brain. Metastases to the brain are the most common intracranial tumours in adults. Substantial progress has been made in the treatment of these tumours, and radiotherapy, surgery, and stereotactic radiosurgery are now established treatments. With aggressive treatment, most patients experience meaningful symptom reduction and extension of life.

BACKGROUND Carcinoma of the urinary bladder accounts for approximately 2% of all malignant tumors and usually spreads through both local invasion and hematogenous dissemination. In the current study, the authors reviewed a large series of patients to determine the nature and frequency of neurologic complications. METHODS In the current study, the authors reviewed the records of 359 patients with bladder carcinoma who were treated at the study institution between 1962–2001. RESULTS Fifty-two patients (14%) were reported to have neurologic complications. Complications resulting from neurologic metastases were relatively infrequent (5%). Seven patients (2%) had lumbosacral plexopathies and 6 patients (2%) had metastatic epidural spinal cord compression. Brain metastases were present in only 4 patients (1%). Nonmetastatic complications were more common than metastatic complications and were comprised of metabolic encephalopathies in 24 patients (7%), peripheral neuropathies in 9 patients (2.5%), cerebral infarctions in 6 patients (2%), and seizures in 5 patients (1%). No cases of neurologic infection or carcinomatous meningitis were reported. CONCLUSIONS The results of the current study demonstrate that neurologic complications are relatively uncommon in patients with bladder carcinoma and that local extension into peripheral nerves or bone, rather than hematogenous dissemination, is the most common cause of neurologic complications resulting from bladder carcinoma. Cancer 2003;97:2267–72. © 2003 American Cancer Society. DOI 10.1002/cncr.11354

PURPOSE: Motexafin gadolinium is a redox mediator that selectively targets tumor cells, is detectable by magnetic resonance imaging (MRI), and enhances the effect of radiation therapy. This lead-in phase to a randomized trial served to evaluate radiologic, neurocognitive, and neurologic progression end points and to evaluate the safety and radiologic response of motexafin gadolinium administered concurrently with 30 Gy in 10-fraction whole-brain radiation therapy for the treatment of brain metastases. PATIENTS AND METHODS: Motexafin gadolinium (5.0 mg/kg/d for 10 days) was administered before each radiation treatment in this prospective international trial. Patients were evaluated by MRI, neurologic examinations, and neurocognitive tests. Prospective criteria and centralized review procedures were established for radiologic, neurocognitive, and neurologic progression end points. RESULTS: Twenty-five patients with brain metastases from lung (52%) and breast (24%) cancer, recursive partitioning analysis class 2 (96%), and an average of 11 brain metastases were enrolled. Neurocognitive function was highly impaired at presentation. Motexafin gadolinium was well tolerated. Freedom from neurologic progression was 77% at 1 year. Median survival was 5.0 months. In 29% of patients, the cause of death was brain metastasis progression. The radiologic response rate was 68%. Motexafin gadolinium’s tumor selectivity was established with MRI. CONCLUSION: (1) Centralized neurologic progression scoring that incorporated neurocognitive tests was implemented successfully. (2) Motexafin gadolinium was well tolerated. (3) Local control, measured by radiologic response rate, neurologic progression, and death caused by progression of brain metastasis, seemed to be improved compared with historical results. A randomized phase III trial using these methods for evaluation of efficacy has just been completed.

Summary Intratumoral (IT) chemotherapy has theoretical advantages in the treatment of brain tumors. The blood–brain barrier is not a factor in drug delivery, and large concentrations of drug can be instilled in the tumor with little systemic toxicity. Bleomycin has activity against gliomas and is a cell cycle selective agent whose efficacy should be enhanced by continuous infusion. We performed a phase I trial to test the feasibility of IT chemotherapy using a refillable, sustained release device, and to determine the maximum tolerable dose of IT bleomycin. The study was an openended dose escalation study. A modified Ommaya reservoir (containing a semipermeable membrane) was implanted with the delivery tube in the center of the tumor. Groups of three patients with recurrent glioblastoma multiforme were entered at progressively higher dose levels of bleomycin. The study closed when all patients at a given starting dose level developed toxicity. Nine patients received doses ranging from 5 to 34 U/wk; the median total cumulative dose was 195 U. No dose limiting systemic toxicity was detected. Neurologic toxicity occurred only at doses above 16 U/wk. We conclude that continuously infused IT bleomycin is well tolerated; the MTD (and recommended dose for a phase II efficacy trial) of IT bleomycin is 16 U/wk.

Over the last 50 years, organ transplantation has developed into a major treatment option for many disorders. Neurologic complications occur frequently following organ transplantation in 30 to 60 percent of transplant recipients. Most neurologic complications, especially those related to direct toxicity from immunosuppressive agents and chronic immunosuppression, are common to all transplant types; other complications are associated predominantly with specific transplant situations.

In the past 15 years, significant advancement has been made in the diagnosis and treatment of brain metastases. The distinction between the management of single and multiple brain metastases is an important one. Although radiotherapy remains a mainstay of treatment, especially in multiple brain metastases, surgical resection and stereotactic radiosurgery also have their place in the management of selected patients. Rarely, interstitial radiation or chemotherapy also may be used to treat brain metastases in the setting of relapse.

Object. This investigation was performed to determine the tolerance and toxicities of split-course fractionated gamma knife radiosurgery (FSRS) given in combination with conventional external-beam radiation therapy (CEBRT). Methods. Eighteen patients with previously unirradiated, gliomas treated between March 1995 and January 2000 form the substrate of this report. These included 11 patients with malignant gliomas, six with low-grade gliomas, and one with a recurrent glioma. They were stratified into three groups according to tumor volume (TV). Fifteen were treated using the initial FSRS dose schedule and form the subject of this report. Group A (four patients), had TV of 5 cm3 or less (7 Gy twice pre- and twice post-CEBRT); Group B (six patients), TV greater than 5 cm3 but less than or equal to 15 cm3 (7 Gy twice pre-CEBRT and once post-CEBRT); and Group C (five patients), TV greater than 15 cm3 but less than or equal to 30 cm3 (7 Gy once pre- and once post-CEBRT). All patients received CEBRT to 59.4 Gy in 1.8-Gy fractions. Dose escalation was planned, provided the level of toxicity was acceptable. All patients were able to complete CEBRT without interruption or experiencing disease progression. Unacceptable toxicity was observed in two Grade 4/Group B patients and two Grade 4/Group C patients. Eight patients required reoperation. In three (38%) there was necrosis without evidence of tumor. Neuroimaging studies were available for evaluation in 14 patients. Two had a partial (≥ 50%) reduction in volume and nine had a minor (> 20%) reduction in size. The median follow-up period was 15 months (range 9–60 months). Six patients remained alive for 3 to 60 months. Conclusions. The imaging responses and the ability of these patients with intracranial gliomas to complete therapy without interruption or experiencing disease progression is encouraging. Excessive toxicity derived from combined FSRS and CEBRT treatment, as evaluated thus far in this study, was seen in patients with Group B and C lesions at the 7-Gy dose level. Evaluation of this novel treatment strategy with dose modification is ongoing.

To determine the tolerance and toxicities of fractionated stereotactic radiosurgery (FSRS) given in combination with conventional external beam radiation therapy (CEBRT).From March 1995 to September 1998, 14 patients with previously unirradiated and unfavorable glioma (malignant glioma, n = 8; unfavorable low-grade glioma, n = 5; and recurrent glioma, n = 1) were stratified into 3 groups according to tumor volume (TV) to determine the initial FSRS dose schedule: Group A (n = 3): TV/= 5 cc (7 Gy x 2 pre- and post-CEBRT]; Group B (n = 6): 5 ccTV/= 15 cc [7 Gy x 2 pre- and 7 Gy x 1 post-CEBRT]; and Group C (n = 5): 15 ccTV/= 30 cc (7 Gy x 1 pre- and post-CEBRT). All patients received CEBRT to 59.4 Gy at 1.8 Gy/fraction. Dose escalation was planned, if toxicity was acceptable.All patients were able to complete CEBRT without interruption or experiencing disease progression. Unacceptable toxicity has been limited to patients in groups B (grade 4, n = 2/6) and C (grade 4, n = 2/5). Eight patients required reoperation, with 3 (38%) having necrosis without evidence of tumor. Eleven patients (79%) have had objective partial (/=50% reduction, n = 2) or minor (20% reduction, n = 9) imaging response. Follow-up ranged from 9 to 51 months (median 15 months), with 7 patients alive at 22-51 months.Imaging response and the ability of these patients with unfavorable intracranial gliomas to complete therapy without interruption or experiencing disease progression is very encouraging. Excessive toxicity of combined FSRS and CEBRT as evaluated thus far in this study was seen for patients with group B/C lesions. Evaluation of this novel treatment strategy with dose modification is ongoing.

Between January 1982 to June 1994, 154 children with non-CNS malignant tumours excluding leukaemias and lymphomas were admitted and treated at the UKMC. Symptomatic (10 cases; 6.5%) and non-symptomatic (2 cases; 1.2%) cranial metastases (calvarial, durai and/or parenchymal) were seen in 12 (7.8%) cases. Among these 12 cases, 7 had intracranial parenchymal metastases (4.5%). Three cases had multiple intracranial parenchymal metastases. Only one case had infratentorial (cerebellar) metastasis. The patients' ages ranged from 1 to 18 years (mean age was 7.3 years). The male ∶ female ratio was 5∶2. While six patients' brain metastases diagnosed during subsequent relapses, one patient first presented with brain metastasis. Time elapsed between the diagnosis of the primary disease and intracranial metastasis ranged from 0 to 755 days (mean 327 days). Histopathological diagnoses were confirmed in 4 cases who had craniotomy and tumour removal. Mean survival following the diagnosis of intracranial lesion was 157 days (ranged from 0 to 412 days). Despite the aggressive treatment, including surgery, chemotherapy and radiotherapy, 6 cases died with progression or relapse of the intracranial disease. In conclusion, the incidence of paediatric intracranial parenchymal metastasis is 4.5%. Prognosis is poor and intracranial disease is the primary cause of death.

Metastatic spinal cord compression (MSCC) is a common problem afflicting cancer patients. It affects 5% to 14% of all patients with cancer, and more than 20,000 cases are diagnosed annually in the United States. Once diagnosed, it is considered to be a medical emergency, and immediate intervention is required with high-dose corticosteroids and radiotherapy, with or without decompressive surgery. Without therapy, MSCC is a source of significant morbidity and mortality, causing pain, paralysis, incontinence, and an overall decline in quality of life. Even with aggressive therapy, results can often be unsatisfactory. Although most patients will die as a result of their underlying cancer within the first year of the diagnosis of MSCC, up to one third will survive beyond 1 year. Therefore, optimal therapy is required to maintain quality of life. Palliative radiotherapy has long been standard in the management of patients with MSCC, but the radiation oncologist is often faced with multiple competing and complex issues. The need to deliver a meaningful radiation dose to the tumor for adequate palliation must be balanced with the necessity of avoiding undue toxicity, the most serious of which is radiation myelopathy. Furthermore, the fractionation scheme must be weighed against the performance status and expected survival of the patient. These issues may explain the wide range of fractionation schemes reported in multiple retrospective analyses, with a total of 30 Gy in 3-Gy daily fractions for 10 days most frequently prescribed. In this issue of the Journal of Clinical Oncology, Maranzano et al report on a phase III, randomized, multicenter trial of two hypofractionation schemes, short course compared with split course, for patients with MSCC. Although there are multiple randomized trials on fractionation schemes for brain and bone metastases, to our knowledge this report is the first such trial for MSCC. The authors should be commended for completing such a difficult trial. Unfortunately, multiple problems are inherent in this study, and readers should be cautious before implementing the results in clinical practice. The explanation of the selection criteria for short life expectancy ( 6 months) of the study patients is incomplete. One can form the interpretation that the main criterion for inclusion was unfavorable histology alone, or favorable histology with neurologic dysfunction or poor performance status. However, this study has included groups of patients who might be anticipated to live significantly longer than 6 months. For example, one of the most significant predictors of short survival for patients with metastatic cancer is poor performance status; yet, 17% of patients in this study had Karnofsky performance status of 80 to 100. Furthermore, patients with radiosensitive tumors (such as lymphoma, seminoma, and myeloma) were included, as were those with histologies that have relatively long survivals after development of metastasis (such as breast and prostate cancer). Although patients with these favorable factors may have been equally distributed between the two treatments, the inclusion of such patients needs to be taken into account to estimate the true efficacy of radiation in the trial. Although only five patients experienced in-field recurrence, 18 patients (10%) lost the ability to walk after therapy. Is it possible that the inclusion of patients with favorable histology and good Karnofsky performance status allowed for longer survivals, and offered just enough time for the late toxicities of hypofractionated radiotherapy to occur? One of the most controversial aspects of this study was the choice of the two treatment arms. The most common JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 15 MAY 2

Five cases of primary spinal column sarcomas are presented. Sarcomas primarily originating from paravertebral soft tissues were excluded. Patients' age ranged from 1 to 14 years (mean 8.4 years). The male:female ration was 2:3. Two patients had Ewing's sarcoma (ES) originating from L5-S1 and L4-5 pedicles, respectively; two patients had mesenchymal chondrosarcoma (MCS) originating from L1-2 pedicles and L5 body, respectively; and one patient had osteogenic sarcoma (OS) of C4 body. All patients clinically presented with pain and progressive weakness of the extremities. The time that elapsed between the onset of symptoms and diagnoses ranged from one to five months. All cases were treated with chemotherapy, radiotherapy and subtotal tumour resection with spinal canal decompression. Two cases received posterior spinal fusion operations. Three patients were alive 10 to 98 months following diagnosis. Only the case with ES of L5-S1 pedicles was in complete remission and off therapy at the 98th postoperative month. The two MCS cases were in partial remission, and were receiving chemotherapy at the time of analysis. These tumours caused similar clinical findings and prognoses, and required combined treatment, which consisted of surgery, radiotherapy and chemotherapy; histologically three different types of malignant tumours are presented in the same category. We preferred surgical decompression and stabilization procedures especially for neurologically symptomatic patients, even if they had extensive tumours with high grades. By spinal canal decompression and stabilisation, we did not intend to cure the disease; however, we intended to provide neurological improvement, spinal stabilisation, improved quality of life, early mobilisation of the patient, and cytoreduction by means of surgical tumour ablation, which could render the chemotherapy more effective.

The management of residual, recurrent, or small skull base meningiomas is controversial. Stereotactic radiosurgery has emerged as an alternative treatment. We report our experience from September 1991 to August 1994 of treatment of 20 such patients [18 females -age 19-82 years, followed for 6-36 months (mean 15.5 months)] with the Leksell Gamma Knife. Nine patients were treated either with recurrent (2 patients-2 operations each) or residual tumor. Twelve patients had skull base, 3 optic nerve, 3 parasagittal, and 1 residual torcular tumor. Mean volume/diameter was 9.172 mm3/25 mm.

Significant advances have been made in the diagnosis and treatment of brain metastases, and the therapeutic nihilism of the past is not warranted for most patients with brain metastases. With currently available treatments, most patients do not die of their brain metastases and usually experience effective palliation of neurologic symptoms and meaningful extension of life.

Neoplastic metastatic epidural spinal cord compression is a common complication of cancer that causes pain and progressive neurologic impairment. The previous standard treatment for this condition involved corticosteroids and radiotherapy (RT). Direct decompressive surgery with postoperative radiotherapy (S + RT) is now increasingly being chosen by clinicians to significantly improve patients’ ability to walk and reduce their need for opioid analgesics and corticosteroids. A cost-utility analysis was conducted to compare S + RT with RT alone based on the landmark randomized clinical trial by Patchell et al. (2005). It was performed from the perspective of the Ontario Ministry of Health and Long-Term Care. Ontario-based costs were adjusted to 2010 US dollars. S + RT is more costly but also more effective than corticosteroids and RT alone, with an incremental cost-effectiveness ratio of US$250 307 per quality-adjusted life year (QALY) gained. First order probabilistic sensitivity analysis revealed that the probability of S + RT being cost-effective is 18.11%. The cost-effectiveness acceptability curve showed that there is a 91.11% probability of S + RT being cost-effective over RT alone at a willingness-to-pay of US$1 683 000 per QALY. In practice, the results of our study indicate that, by adopting the S + RT strategy, there would still be a chance of 18.11% of not paying extra at a willingness-to-pay of US$50 000 per QALY. Those results are sensitive to the costs of hospice palliative care. Our results suggest that adopting a standard S + RT approach for patients with MSCC is likely to increase health care costs but would result in improved outcomes.

Over the last thirty years, organ transplantation has become a practical treatment option for many otherwise fatal diseases. New immunosuppressive agents, advances in tissue matching, and improvements in surgical technique have increased both the number and type of transplants performed. Kidney, bone marrow, heart, lung, liver, and pancreas transplants are now used regularly in the treatment of end-stage disease. However, these advances have come at a price. Transplant recipients are subject to numerous complications, many of which involve the nervous system. Depending on the type of organ transplanted, 30 to 60% of transplant recipients experience neurological problems. Most neurological complications, especially those related to immunosuppression, are common to all transplant types; other complications are associated predominantly with specific transplant types. This report reviews the general categories of neurological complications as well as the specific problems associated with each kind of transplant.

Purpose : This paper describes a system for the implantation of rigid stainless steel afterloading tubes into the brain using a stereotaxic head frame for both localization and treatment. Methods and Materials : The stereotaxic frame is attached to the skull throughout the treatment, and the afterloading tubes are both rigid and fixed to the frame. The source positions are therefore fixed relative to the skull throughout the irradiation. Design and construction of templates, afterloading tubes and clamps are discussed in detail. Results : The rigidity of the resulting implant provides accurate and immobile positioning of the planned isodose distribution relative to the defined treatment volume and makes it possible to carefully and rapidly plan a source loading which will best cover the volume of interest. The source template is not in contact with the patient at any time. The afterloading tubes are held strictly parallel during treatment, allowing for rapid and versatile preplanning prior to surgical placement. Placement options are enhanced by using a set of rotating templates. Conclusion : This system has been used for over 60 procedures without any mechanical or safety problems and has provided a significant improvement in both the speed and confidence of localization and treatment planning. There are significant advantages of such a system for High Dose Rate Afterloading Brachytherapy.

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 ± 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. Question Does surgical resection in addition to WBRT improve outcomes when compared with WBRT alone? Target population This 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). Recommendation Surgical resection plus WBRT versus WBRT alone Level 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.

Intracranial hemorrhages are a recognized but relatively uncommon complication of brain tumors. Metastatic tumors are more often associated with hemorrhages than are primary tumors. The types of hemorrhages found include intraparenchymal, subarachnoid, subdural, and epidural. Treatment must be directed at both the hemorrhage and the underlying tumor.

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. 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.

Summary Metastatic epidural spinal cord compression (MESCC) occurs when cancer metastasises to the spine or epidural space and causes secondary compression of the spinal cord. MESCC is a common complication of malignancy that affects almost 5% of patients with cancer. The most common symptom is back pain. MESCC is a medical emergency that needs rapid diagnosis and treatment if permanent paralysis is to be prevented: the diagnosis of MESCC is best made with MRI; and corticosteroids, radiation therapy, and surgery are all established treatments. Future research will focus on prevention, improving detection, and the development of new treatments.

Whole-brain radiation therapy (WBRT) is the mainstay of treatment for most patients with intracerebral metastases. It is useful for most newly diagnosed tumors and sometimes also as salvage therapy for recurrent tumors.