Evaluating innovation. Part 2: Development in neurosurgery.

OBJECT Patients, practitioners, payers, and regulators are advocating for reform in how medical advances are evaluated. Because surgery does not adhere to a standardized developmental pathway, how the medical community accepts a procedure remains unclear. The authors developed a new model, using publication data and patterns, that quantifies this process. Using this technique, the authors identified common archetypes and influences on neurosurgical progress from idea inception to acceptance. METHODS Seven neurosurgical procedures developed in the past 15-25 years were used as developmental case studies (endovascular coil, deep brain stimulation, vagus nerve stimulation, 1,3-bis(2-chloroethyl)-l-nitrosourea wafer, and 3 radiosurgery procedures), and the literature on each topic was evaluated. A new metric the authors termed "progressive scholarly acceptance" (PSA) was used as an end point for community acceptance. PSA was reached when the number of investigations that refine or improve a procedure eclipsed the total number of reports assessing initial efficacy. Report characteristics, including the number of patients studied, study design, and number of authoring groups from the first report to the point of PSA, were assessed. RESULTS Publication data implicated factors that had an outsized influence on acceptance. First, procedural accessibility to investigators was found to influence the number of reports, number of patients studied, and number of authoring groups contributing. Barriers to accessibility included target disease rarity, regulatory restrictions, and cost. Second, the ease or difficulty in applying a randomized controlled trial had an impact on study design. Based on these 2 factors, 3 developmental archetypes were characterized to generally describe the development of surgery. CONCLUSIONS Common surgical development archetypes can be described based on factors that impact investigative methods, data accumulation, and ultimate acceptance by society. The approach and proposed terminologies in this report could inform future procedural development as well as any attempts to regulate surgical innovation.

[Chemotherapeutic wafers in treatment of malignant cerebral glioma. Assessment of a Cochrane review]. / Kemoterapi-impraegnerede "wafers" i behandlingen af maligne gliomer i hjernen. Gennemgang af et Cochrane-review.

The present Cochrane review deals with implantation of chemotherapeutic wafers in the surgical cavity after resection of a malignant glioma. The authors found two controlled, randomised studies concerning this treatment modality after first-time surgical treatment and one study dealing with treatment of recurrent tumour. An effect was shown in the first with an increase in median survival of 2 months equivalent to the survival seen after standard (concomitant) treatment. No effect was shown in recurrent tumour.

Risk management in the treatment of malignant gliomas with BCNU wafer implants.

Implantation of BCNU wafers (Gliadel®) into the resection cavity has demonstrated a survival benefit for patients with newly diagnosed malignant gliomas. The follow-up of two phase III trails has further shown that the number of long-term survivors was significantly increased by BCNU wafer treatment. BCNU wafer implantation may be integrated into current multimodal first line strategies. In the setting of recurrent disease BCNU wafer implantation has also shown a survival benefit and now extends the treatment options in a patient population that typically has undergone extensive pretreatment. An analysis of the literature has helped to clearly identify the risks associated with topic BCNU treatment. Here we summarize the incidence and time course of adverse events associated with local chemotherapy and propose solutions. The growing body of experience with BCNU wafer implantation may serve as a basis to develop adequate risk management strategies with regard to patient selection, surgical techniques, and follow-up schedules.

Assessment of a balloon-tipped catheter modified for intracerebral convection-enhanced delivery.

Numerous improvements in the understanding of the biology of primary brain tumors have been reported. The resultant application of this information to the therapy of these lesions offers promising alternatives. For any of a number of reasons delivery of these therapies to the target neoplasm can be challenging. Convection enhanced delivery has been established as a modality that has been shown to circumvent some of the impediments to treatment agent delivery. This report described the preliminary preclinical use of a balloon tipped catheter with a channel built in for infusion of therapy directly into the brain. A series of 10 canines were studied using bolus and continuous infusions with the balloon either inflated or deflated. The infusates contained gadolinium to allow imaging of the convection process. The character of the cerebral penetration is described ranging from minimal cerebral penetration with uninflated balloons used with bolus injections to extensive bilateral penetration using inflated balloons and continuous infusions. This data demonstrates the feasibility and potential value of such a system and warrants a more detailed analysis of the device using a wider variety of infusion parameters, assessment of larger infusate molecule sizes likely to be solely dependent on convection and direct comparison to standard catheter convection techniques.

Carmustine implants for the treatment of newly diagnosed high-grade gliomas: a cost-utility analysis.

BACKGROUND: High-grade gliomas are aggressive brain tumours that are extremely challenging to treat effectively. The intracranial implantation of carmustine wafers (BCNU-W), which delivers chemotherapy directly to the affected area, may prolong survival in this population. However, no attention has yet been paid to the economic implications of BCNU-W in this setting. OBJECTIVE: To investigate the cost effectiveness of BCNU-W as an adjunct to surgery followed by radiotherapy, compared with surgery plus radiotherapy alone. Newly diagnosed, operable grade III and IV gliomas in a population with a mean age of 55 years were considered. METHODS: A Markov cost-utility model was developed in Microsoft Excel, adopting a UK NHS perspective. Transition probabilities and cost data (year 2004 values) were obtained from published literature or expert opinion. The model incorporated utility values, obtained from members of the public, reflecting the quality of life associated with high-grade glioma. The effects of uncertainty were explored through extensive one-way and probabilistic sensitivity analysis. RESULTS: Surgery with the implantation of BCNU-W followed by radiotherapy costs pound sterling 54 500 per additional QALY gained when compared with surgery plus radiotherapy alone. Probabilistic sensitivity analysis shows a <10% probability that BCNU-W would be considered cost effective at a willingness-to-pay threshold of pound sterling 30 000 per QALY. Although model outputs were sensitive to alterations in several key parameters, the incremental cost effectiveness of the intervention remained above pound sterling 30 000 per QALY in all analyses. CONCLUSION: Compared with usual care for the treatment of newly diagnosed high-grade gliomas, BCNU-W is unlikely to be considered a cost-effective use of healthcare resources when judged by the standards commonly adopted in England and Wales. However, the dreadful prognosis of the condition and the paucity of alternative therapies are additional issues that healthcare commissioners may choose to take into account when considering an adoption decision.

The effectiveness and cost-effectiveness of carmustine implants and temozolomide for the treatment of newly diagnosed high-grade glioma: a systematic review and economic evaluation.

OBJECTIVES: To assess the clinical and cost-effectiveness of adjuvant carmustine wafers (BCNU-W) and also of adjuvant and concomitant temozolomide (TMZ), compared with surgery with radiotherapy. DATA SOURCES: Electronic databases were searched up to August 2005. REVIEW METHODS: Included trials were critically appraised for key elements of internal and external validity. Relevant data were extracted and a narrative synthesis of the evidence produced. Where possible, data on absolute survival at a fixed time point were meta-analysed using a random effects model. A Markov (state transition) model was developed to assess the cost-utility of the two interventions. The model compared BCNU-W or TMZ separately with current standard treatment with surgery and radiotherapy. The simulated cohort had a mean age of 55 years and was modelled over 5 years. RESULTS: Two randomised controlled trials (RCTs) (n = 32, n = 240) and two observational studies of BCNU-W compared with placebo wafers as adjuvant therapy to surgery and radiotherapy for newly diagnosed high-grade glioma were identified. All the studies were in adults and provided data on 193 patients who had received BCNU-W. The RCT findings excluded under 65-year-olds and those with a Karnofsky Performance Status of less than 60. The largest multi-centre RCT suggested a possible survival advantage with BCNU-W among a cohort of patients with grade III and IV tumours, adding a median of 2.3 months [95% confidence interval (CI) -0.5 to 5.1]. However, analysis using per-protocol, unstratified methods shows this difference to be not statistically significant (HR 0.77, 95% CI 0.57 to 1.03, p = 0.08). Long-term follow-up suggests a significant survival advantage using unstratified analysis. No difference in progression-free survival (PFS) was demonstrated. Subgroup analysis of those with grade IV tumours also showed no significant survival advantage with BCNU-W [hazard ratio (HR) 0.82, 95% CI 0.55 to 1.11, p = 0.20, unstratified analysis]. It is estimated that the cost of surgery and radiotherapy, with follow-up, treatment of adverse effects and end of life care is around 17,000 pounds per patient. Treatment with BCNU-W adds an additional 6600 pounds. Across the modelled cohort of 1000 patients, use of BCNU-W costs an additional 6.6 million pounds and confers an additional 122 quality-adjusted life-years (QALYs). On average, that is 6600 pounds per patient for 0.122 QALYs (6.3 quality-adjusted life-weeks). The base-case incremental cost-effectiveness ratio (ICER) is 54,500 pounds/QALY. In probabilistic sensitivity analyses, BCNU-W was not cost-effective in 89% of the simulations assuming a willingness to pay threshold of 30,000 pounds/QALY. In 15% of simulations, BCNU-W was dominated (i.e. did more harm than good, conferring fewer QALYs at greater cost). The cost-effectiveness acceptability curve (CEAC) suggests that it is very unlikely to be the most cost-effective option at normal levels of willingness to pay (11% probability at 30,000 pounds/QALY), only becoming likely to be the most cost-effective option at much higher levels of willingness to pay (50% probability at 55,000 pounds/QALY). Two RCTs (n = 130, n = 573) and two observational studies were included, giving evidence for 429 adult patients receiving TMZ. Currently, TMZ is licensed for use in those with newly diagnosed grade IV gliomas only. The RCTs excluded those with lower performance status and, in the larger RCT, those older than 70 years. TMZ provides a small but statistically significant median survival benefit of 2.5 months (95% CI 2.0 to 3.8), giving an HR of 0.63 (95% CI 0.52 to 0.75, p < 0.001). At 2 years, 26.5% of patients treated with TMZ were alive compared with 10.4% of those in the control arm. Median PFS is also enhanced with TMZ, giving a median 1.9 months' advantage (95% CI 1.4 to 2.7, p < 0.001). No analysis of the subgroup of patients with confirmed grade IV tumours was undertaken. Subgroup analysis of patients by O6-methylguanine-DNA methyltransferase (MGMT) activity showed a significant treatment advantage for those with reduced MGMT activity but not for those with normal activity, although this analysis was based on a selected sample of patients and the test used has proved difficult to replicate. A median gain of 6.4 (95% CI 4.4 to 9.5) more life-months is seen with TMZ among those with reduced MGMT, giving an HR of 0.51 (p < 0.007). PFS is increased by a median of 4.4 months (95% CI 1.2 to 6.3), giving an HR of 0.48 (p = 0.001). The model shows a cost per patient for being treated with surgery, radiotherapy and including adverse effects of treatment and end of life care of around 17,000 pounds per patient. TMZ in the adjuvant and concomitant phase adds an additional cost of around 7800 pounds. Across the modelled cohort of 1000 patients, use of TMZ costs an additional 7.8 million pounds and confers an additional 217 QALYs. For the average patient this is 7800 pounds for an additional 0.217 QALYs (11 quality-adjusted life-weeks). The base-case ICER is 36,000 pounds/QALY. Probabilistic sensitivity analyses shows that TMZ was not cost-effective in 77% of the simulations. The CEAC suggests that there is a 23% chance that TMZ is the most cost-effective option at a willingness to pay level of 30,000 pounds/QALY, rising to be more cost-effective than no TMZ at slightly higher levels (50% probability at 35,000 pounds/QALY). CONCLUSIONS: BCNU-W has not been proven to confer a significant advantage in survival for patients with grade III tumours when treated with the drug, compared with placebo. There does not appear to be a survival advantage for patients with grade IV tumours. No increase in PFS has been shown. Limited evidence suggests a small but significant advantage in both overall survival and PFS with TMZ among a mixed population with grade IV and grade III (7-8%) tumours. However, it remains unclear whether this is true in grade IV tumours alone. On the basis of best available evidence, the authors consider that neither BCNU-W nor TMZ is likely to be considered cost-effective by NHS decision-makers. However, data for the model were drawn from limited evidence of variable quality. Tumour type is clearly important in assessing patient prognosis with different treatments. Grade IV tumours are commonest and appear to have least chance of response. There were too few grade III tumours included to carry out a formal assessment, but they appear to respond better and drive results for both drugs. Future use of genetic and biomarkers may help identify subtypes which will respond, but current licensing indications do not specify these. Further research is suggested into the effectiveness of these drugs, and also into areas such as genetic markers, chemotherapy regimens, patient and carer quality of life, and patient views on survival advantages vs treatment disadvantages.

The surgical bed after BCNU polymer wafer placement for recurrent glioma: serial assessment on CT and MR imaging.

OBJECTIVE: The objective of our study was to describe the CT and MR imaging appearances of the surgical bed in the brains of patients receiving biodegradable polymers impregnated with N, N'1, 3-Bis-(2-chloroethyl)-N-nitrosourea (BCNU) for recurrent glioma and to determine whether patients receiving placebos could be differentiated from those receiving BCNU based on the pattern and growth kinetics of tumor recurrence. MATERIALS AND METHODS: The CT and MR images of 20 patients who underwent surgery for resection of recurrent high-grade gliomas and placement of intratumoral wafers (11 received BCNU polymer wafers, nine received control wafers) were analyzed for wafer appearance, volume of gas in the tumor bed, and volume of enhancement on serial scans. RESULTS: Wafers appeared as linear hyperdense structures on CT and as linear low-signal-intensity structures on MR imaging and caused no significant enhancement. In the BCNU polymer group, gas volume was 4.0 +/- 3.4 cm(3) (mean +/- SD), whereas gas volume was 1.6 +/- 3.0 cm(3) for the placebo group (Mann-Whitney test, p = 0.03). A trend toward linear rather than exponential recurrent tumor growth was identified for the BCNU polymer group but not for the placebo group. CONCLUSION: BCNU polymer wafers have a specific appearance on CT and MR imaging with which radiologists should be familiar: gas in the surgical bed is an expected transient finding, and tumor regrowth in patients receiving BCNU polymer wafers appeared to occur at a slower rate than in those receiving the placebo.

Favorable treatment outcome in non-Hodgkin's lymphoma patients with "poor" mobilization of peripheral blood progenitor cells.

Our purpose was to evaluate the outcome and costs of high-dose chemotherapy and autologous peripheral blood progenitor cell (PBPC) transplantation in patients with the inability to mobilize sufficient numbers of PBPCs to allow rapid engraftment after PBPC transplantation. We treated 172 consecutive non-Hodgkin's lymphoma (NHL) patients with cyclophosphamide and granulocyte colony-stimulating factor followed by apheresis to collect PBPCs. The cells were separated on a Percoll gradient and purged with monoclonal antibodies and complement. The patients were categorized as "good" mobilizers if a collection of > or =2 x 10(6) CD34+ cells/kg was obtained (n = 138, 80%) or "poor" mobilizers if <2 x 10(6) CD34+ cells/kg were obtained (n = 34, 20%). With a median follow-up of 3.5 years, there is no statistically significant difference in actuarial event-free survival, overall survival, or relapse for good mobilizers compared with poor mobilizers. However, there was a trend toward increasing nonrelapse, transplantation-related mortality of 11.8% for poor mobilizers versus 3.6% for good mobilizers (P = .08) and early death from all causes including relapse within 120 days (poor 20.6% versus good 8.7%, P = .06). The total cost for bone marrow transplantation-related care was significantly higher, at $140,264 for poor mobilizers versus $80,833 for good mobilizers (P = .0001). The population of patients with NHL who mobilize PBPCs poorly into the circulation have a higher cost for posttransplant support. However, there is no significant difference in relapse, event-free survival, or overall survival for such patients compared with those who mobilize PBPCs easily.

Stem cell transplantations in patients with malignant lymphoma: costs in a Dutch university hospital in the period 1984-1995.

In the past 15 years, perspectives on treatment of patients with relapsed non-Hodgkin's lymphoma have changed. This has had important consequences for the costs of treatment. We conducted a retrospective study comparing the costs of four different treatment modalities in a university hospital in The Netherlands. The first group of patients received an autologous bone marrow transplantation (ABMT) and was kept in reverse barrier nursing. Their average total treatment costs amounted to US$26,539. Patients in the second group also received an ABMT but stayed on the normal hematology ward. The total average treatment costs for this group were US$20,806. In the third group, patients were transplanted with whole blood. Their average total treatment costs amounted to US$17,000. Patients in the fourth group received transplantation of autologous PBPC and their average total treatment costs were US$14,205. The decline in costs over time was mainly due to shorter hospitalization, less blood transfusions, and less parenteral nutrition. These factors also likely led to an improvement in patients' quality of life. The results of this study show that the progression in stem cell transplantation (SCT) techniques has been accompanied by significant benefits for patients and a decrease in costs.

Assessment of pulmonary and cardiac function after high dose chemotherapy with BEAM and peripheral blood progenitor cell transplantation.

BACKGROUND: Limited information is available regarding the cardiac and pulmonary effects of high dose chemotherapy (HDCT) and autologous peripheral blood progenitor cell (PBPC) transplantation. METHODS: The authors evaluated cardiac and pulmonary function after BEAM (BCNU 300 mg/m2, etoposide 400 mg/m2/day x 3 days, cytosine arabinoside 200 mg/m2/day x 4 days, and melphalan 140 mg/m2), HDCT, and PBPC transplantation in 26 patients with non-Hodgkin's lymphoma or Hodgkin's disease. Therapy prior to BEAM included doxorubicin (25 patients), bleomycin (6 patients), and mediastinal irradiation (4 patients). All patients had pulmonary function tests (PFTs) and equilibrium radionuclide angiography before and at a median of 57 weeks after transplantation. RESULTS: Prior to high dose therapy, 8 patients had abnormal PFTs, including 6 with a diffusing capacity of the lung for carbon monoxide (DLCO) <70% of predicted value. At the time of reevaluation after HDCT, all patients included in the study were in complete remission, and none had received additional therapy after transplantation. At a median of 77 weeks after transplantation, none of the patients had cardiac or pulmonary symptoms. Moreover, there were no significant changes in total lung capacity, forced vital capacity, forced expiratory volume in 1 second/forced vital capacity, DLCO, or left ventricular ejection fraction values when compared with baseline studies. CONCLUSIONS: The authors concluded that HDCT with BEAM and PBPC transplantation did not result in significant cardiac or pulmonary toxicity, even in patients with borderline pretransplantation PFT values. Further studies of patients undergoing HDCT and PBPC transplantation are needed.

Updated analysis of an outpatient chemoimmunotherapy regimen for treating metastatic melanoma.

PURPOSE: Aggressive inpatient chemoimmunotherapy protocols for metastatic melanoma have yielded encouraging response rates but have required lengthy hospitalizations. To reduce or eliminate the need for hospitalization, we have developed an outpatient chemoimmunotherapy regimen and assessed its efficacy and toxicity in 53 patients treated at the University of Washington Medical Center. PATIENTS AND METHODS: Eligible patients with measurable metastatic melanoma received carmustine (150 mg/m2 every 6-8 weeks) and dacarbazine (660 mg/m2) and cisplatin (75 mg/m2) every 3 to 4 weeks in an infusion center plus tamoxifen (20 mg/day). Patients self-administered subcutaneous recombinant interleukin-2 (rIL-2) at 3 MIU/m2/day on days 3 to 9, and recombinant interferon alfa-2a (rIFN-alpha 2a) at 3 MIU on day 3 and at 5 MIU/m2/day on days 5, 7, and 9. Maintenance rIFN-alpha 2a was self-administered subcutaneously at 5 MIU/m2 tiw for 12 months after complete or stable partial response. Response and survival were assessed. RESULTS: Fifty-three patients (median age = 49 years) have received 181 cycles. To date, there have been 10 complete responses (19%) lasting 2 to 28+ months and 12 partial responses (23%) lasting 2 to 11 months, for an overall response rate of 42% (95% confidence interval, 28%-55%). The median overall survival was 12 months. Grade 3/4 vomiting occurred in 32% of cycles, but hospitalization for supplemental intravenous fluids was required in only 11% of cycles for a median of 3 days. Grade 4 thrombocytopenia and neutropenia occurred in 9% and 8% of cycles, respectively. Grade 3 renal dysfunction occurred in only one cycle and was reversible. CONCLUSION: A chemoimmunotherapy regimen for patients with metastatic melanoma has been defined that is well tolerated on an outpatient basis and is associated with a median survival comparable to that with aggressive inpatient chemoimmunotherapy regimens.

Economic analysis of prophylactic G-CSF after mini-BEAM salvage chemotherapy for Hodgkin's and non-Hodgkin's lymphoma.

The objectives of this study were to compare the costs of managing lymphoma patients who underwent mini-BEAM salvage chemotherapy with G-CSF prophylactic support against a group of similar patients without growth factors. Methods used included: 1) A retrospective chart review was conducted to estimate the average length of hospitalization and resource consumption for the management of fever and neutropenia in the two groups of patients and 2) An economic analysis was then performed from a hospital perspective which considered only institutional resource utilization. Costs of antibiotic support and monitoring, lab tests as well as G-CSF were calculated. Results demonstrated that overall, patients who received prophylactic G-CSF after chemotherapy required 2 fewer hospital days compared to controls. The administration of G-CSF resulted in a savings of approximately $1580/patient relative to control. When the initial G-CSF expenditure was included in the analysis, the total net cost/patient was similar between the two groups. In conclusion, the results of the current study support the routine use of G-CSF in patients receiving salvage chemotherapy with mini-BEAM. The initial G-CSF expenditure would be offset by reduced hospitalization.

The assessment of response of murine transplantable colon tumors to combination chemotherapy.

The mouse adenocarcinoma of the colon (MAC) system, which has been shown to be a good model for human colorectal carcinoma in terms of its chemosensitivity, was tested with two modified human protocols (MeCCNU + 5 FU, BCNU + 5 FU) in an attempt to evaluate its suitability as a model for developing new regimens of combination chemotherapy for treating patients with colorectal carcinoma. This attempted evaluation raised problems regarding, firstly, the length of time available before tumours became too large in control and non-responding hosts to maintain adequate mobility and, secondly the assessment of response to the drugs. The commencement of drug administration 3 days after transplantation and the assessment of response by measuring delay in time for tumor growth to reach a given volume, with the results analysed by Gehan's (generalised Wilcoxon) test, gave a workable method of evaluation. This method is presented as being suitable for use in the study of transplantable solid tumor lines as models for combination chemotherapy.

Prediction of BCNU pulmonary toxicity in patients with malignant gliomas: an assessment of risk factors.

Symptomatic pulmonary disease occurred in 20 per cent of 93 patients with anaplastic gliomas being treated with carmustine (BCNU). An analysis of the variables has revealed a relation between the occurrence of pulmonary toxicity on the one hand, and the total cumulative dose of BCNU, the number of cycles over which the BCNU was administered, the history of lung disease, the patient's age, and the platelet-count nadir after the first course of BCNU on the other. An equation has been generated that allows prediction of pulmonary toxicity during the course of therapy with BCNU with 80 per cent accuracy. Pretreatment analysis of individual cases should allow safe use of BCNU and prevention of most of the serious pulmonary complications caused by this drug.