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Journal of Clinical Oncology, Vol 24, No 7 (March 1), 2006: pp. 1136-1144
© 2006 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2005.03.1179
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Quality of Randomized Controlled Trials Reporting in the Primary Treatment of Brain Tumors

Rose Lai, Rong Chu, Michael Fraumeni, Lehana Thabane

From the Department of Clinical Epidemiology and Biostatistics, and Department of Computing and Software, McMaster University; Juravinski Cancer Center; and Center for the Evaluation of Medicine, St Joseph Healthcare, Hamilton, Ontario, Canada.

Address reprint requests to: Rose Lai, MD, MSc, The Neurological Institute of Columbia University, Brain Tumor Center, 710 W 168th St, Room 204, New York, NY 10032; e-mail: rlai{at}neuro.columbia.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
PURPOSE: To assess the reporting quality of randomized controlled trials (RCTs) in the primary treatment of brain tumors and to identify significant predictors of quality.

PATIENTS AND METHODS: Two investigators searched MEDLINE, EMBASE, and bibliographies of retrieved articles for RCTs in the primary treatment of brain tumors published between January 1990 and December 2004. We assessed the quality of overall reporting and key methodologic factors reporting (allocation concealment, blinding, and intention to treat [ITT]). Two investigators also rated articles independently using items from the revised Consolidated Standards of Reporting Trials statement. A generalized estimated equation was used to generate regression models that identified significant factors associated with quality of reporting.

RESULTS: We retrieved 74 relevant RCTs that randomly assigned 14,498 brain tumor patients. The quality of overall reporting has improved during the last 15 years, but eight of the 15 methodologic items were reported in less than 50% of trials. In the appraisal of the reporting quality of key methodologies, allocation concealment, blinding, and adherence to the ITT principle were reported in less than 30% of articles. Multivariable regression models revealed that an impact factor more than 1.66, publication after 1995, and sample size more than 280 were significant factors associated with better overall reporting, whereas complete industrial funding, impact factors more than 2.64, and positive primary outcomes were predictors of higher ratings of the three most important methodologic qualities.

CONCLUSION: Despite improvement in general reporting quality, key methodologies that safeguard against biases may still benefit from better description. Significant factors associated with better reporting may act as surrogates for other characteristics.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
Adult brain tumors are relatively rare diagnoses with poor prognoses.1 Advances in their treatments, especially those of glioma, have been slow because the tumors are diffusely infiltrating and molecularly heterogeneous, rendering local therapy and conventional chemotherapy ineffective in sustaining tumor control. The challenge of penetrating the blood-brain barrier adds to the obstacles of finding efficacious agents. Nevertheless, there have been some major therapeutic breakthroughs recently via high-quality randomized controlled trials (RCTs).2 Similar to other areas of medicine, RCTs remain the gold standard for evidence-based practice in neuro-oncology because of their established validity in drawing causal inferences.

Many physicians judge the merit of RCTs based on the quality of published reports. Although it is an imperfect proxy for true methodologic quality, reporting quality continues to influence our interpretation of evidence for a number of reasons. First, contacting authors to clarify methodologic issues can be time consuming and inconvenient. Second, practice guideline developers often rely on the quality of publications to make their recommendations, and published RCTs are the most important resources. Third, RCTs of sufficient quality are needed to conduct unbiased meta-analysis.3 Furthermore, the quality of reporting is essential for guiding journal peer-review decisions.

To our knowledge, no one has systematically evaluated the quality of RCT reporting in the primary treatments of brain tumors. Because neuro-oncology is an evolving area of medicine, this evaluation may help to facilitate the future development of evidence-based guidelines and practice by identifying reporting deficiencies that can benefit from improvement. At present, there are few guidelines for the treatments of brain cancers, and clinical practice may not follow the best evidence.4 In addition, good reporting quality ensures the validity of meta-analysis, which is particularly useful in neuro-oncology because many individual RCTs are underpowered to detect small effect sizes. Therefore, we conducted this observational study to appraise the quality of RCT reporting in brain tumor therapy. Our goals were to assess the overall quality of published articles using standard guidelines, to specifically evaluate the reporting of those key methodologic qualities that safeguard against biases, and to investigate factors associated with better reporting quality.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 Appendix
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
Study Selection
We searched MEDLINE, EMBASE, and bibliographies of retrieved articles for RCTs in brain tumor treatments published between January 1, 1990, and December 31, 2004, using the terms "brain neoplasms," "brain tumors," "brain cancers," and "randomized controlled trials." We included phase III RCTs published in English on the primary treatment of adult brain tumors and considered all histologic types. The exclusion criteria were RCTs on secondary treatments (eg, treatment of symptoms from tumor or therapy), and phase II RCTs, because they often require additional studies to provide conclusive evidence.5 When the same trial was published more than once, we retained the report based on the primary outcome or the article with the most updated results. Therefore, each study represented a unique trial. Two trained investigators (R.L. and M.F.) independently retrieved articles based on the above inclusion and exclusion criteria. Any discrepancies were resolved through consensus and reference to the abstracts or articles.

Rating of Overall Reporting Quality
Given that we defined quality of reporting as the extent to which the rationale, method, conduct, and results of the trial are reported, we adopted 15 relevant items from the revised Consolidated Standards of Reporting Trials (CONSORT) statement for our appraisal. CONSORT items were chosen because a lack of their reporting has been associated with estimates of increased levels of bias .6 Each item was rated yes (1 point) or no (0 points), and the 15 scores were then combined to form the overall reporting quality score (range, 0 to 15 points). In this evaluation, we segregated out the three most important measures of RCT methodology for a separate assessment (see Rating of Key Methodologic Qualities) because a study found deficiencies in the reporting of key methodologic factors even among articles with high overall reporting scores.7 Two trained investigators (R.L. and R.C.) who were blinded to each other's ratings abstracted data independently into a standardized data abstraction form, which was pilot tested on 15 studies and subsequently was revised. Disagreements were resolved by discussion, and an overall chance-adjusted, inter-rater agreement was calculated.

Rating of Key Methodologic Qualities
We used the reporting of allocation concealment, blinding, and analysis that adhered to the intention-to-treat principle (ITT) as key methodologic domains because omission of these three qualities has been associated with bias and distortions of treatment effect estimates by 20% to 45%.3,8,9 Allocation concealment is the masking of upcoming treatment assignments before random assignment from the individuals who enrolled participants onto RCTs. The frequency of its reporting may differ, depending on the methods considered to be adequate.10 In this study, the definition of adequate concealment included central randomization; numbered, coded vehicles; and opaque, sealed, and sequentially numbered envelopes. Inadequate methods included predictable sequences of allocation, such as the use of alternation, date of birth, and patient record number. These criteria were similar to those recommended for Cochrane reviews.11

Similarly, ITT may have different meanings for different investigators. In this study, we adopted the most common interpretation, which is the inclusion of all patients randomly assigned in the analysis (regardless of whether they actually satisfied the entry criteria; eg, central neuropathology review), the treatment actually received, and subsequent withdrawal or deviation from the protocol.12 To examine further the application of ITT analysis, we characterized the handling of deviations from randomized allocation, false inclusions, and missing outcomes for each trial.

In the assessment of blinding, the terms double blind and single blind were judged insufficient for readers to determine who was blinded, given that blinding can occur at the levels of patients, treating physicians, judicial outcome assessors, and data analysts.13 However, blinding of patients or treating physicians is often not feasible in many RCTs of brain tumor therapy because trials may involve the comparisons of different treatment modalities or therapeutics with diverse adverse effect profiles. Nevertheless, the judicial outcome assessors (central neuro-radiology review) who evaluate progression-free survival or time to progression could often be blinded. Therefore, we considered blinding to have occurred if trials specified at least one blinded group. In addition, we compared blinding rates that are feasible with those actually achieved for patients, treating physicians, and judicial outcome assessors.

For each of the above-described three factors, we adopted relevant items from the CONSORT statement for evaluation. Each item was scored with 1 point if the method was appropriate and received 0 points if the reporting was unclear or the method was inappropriate. A combined key methodologic index score was calculated for each trial by combining the scores of these three factors (possible range, 0 to 3). An inter-rater agreement was calculated for each key methodology.

Statistical Analyses
The percentage of trials that scored yes to each CONSORT item and the associated 95% CI were tabulated. Chance-adjusted inter-rater agreements were calculated using the Cohen's {kappa} statistics. We judged agreement as poor if {kappa} ≤ 0.2; fair if 0.21 ≤ {kappa} ≤ 0.4; moderate if 0.41 ≤ {kappa} ≤ 0.6; substantial if 0.61 ≤ {kappa} ≤ 0.8; and good if {kappa} ≥ 0.8.14

To identify factors associated with overall quality of reporting, we used the overall quality reporting score as the outcome variable. We first performed univariate analyses using trial characteristics as covariates. Variables that were significant at the {alpha} ≤ .1 level were entered into the multivariable model. Nonsignificant covariates (P > .05) in the multivariable model were deleted using stepwise backward elimination. A handful of journals frequently published RCTs in brain tumors, and there is likely a correlation in manuscript quality within each journal. Therefore, for the regression analyses, we used generalized estimated equations (GEEs), which deal accurately with clustered data, to handle the possible correlation in quality scores for reports published by the same journal.15 The GEE correlation matrix is exchangeable, and to protect from mis-specification, we used the modified Sandwich estimate of variance, which is robust to any form of within-cluster correlation. Because rating scores did not seem to be normally distributed and were non-negative counts, we used the negative binomial and Poisson distributions for the GEE. Only results obtained from the Poisson distribution are presented here because both distribution assumptions led to the same findings. To study predictors of key methodologic factor reporting, the same procedure was repeated using the key methodologic index score as the outcome variable. The goodness of fit of regression models was measured using R2MARG, which is the proportion of variance in the outcome that is explained by the GEE model.16 All statistical analyses were performed using STATA software, Version 8 (STATA Corp, College Point, TX).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 Appendix
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
Characteristics of Retrieved RCTs
The RCT selection process is outlined in Figure 1. The inter-rater agreement {kappa} between the two investigators who selected articles was 0.86 (95% CI, 0.81 to 0.91). Table 1 summarizes the characteristics of included trials. A total of 14,498 patients were randomly assigned, and of the 74 RCTs that formed the basis of this study, more than 90% were therapeutic trials on glioma and CNS metastases. The 45 RCTs on glioma can be further subclassified into four trials on low-grade glioma, 37 trials on malignant glioma, and four trials on a mixture of low- and high-grade histology. Six journals published more than half of all brain tumor RCTs. The primary end point was survival for 63 studies (85.1%) and response rate for the remaining 11 trials (14.9%).


Figure 1
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  		Fig 1. A flow diagram of randomized controlled trials (RCTs) selection.

 

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  		Table 1. Characteristics of Included Brain Tumor RCTs

 
Ratings of Overall Quality and Key Methodologic Qualities
The ratings of overall quality of reporting are listed in Table 2. The overall inter-rater agreement {kappa} was 0.83 (95% CI, 0.79 to 0.87). When the 74 RCTs are considered together, eight of the 15 items were reported in less than 50% of studies. Table 2 also lists the results for CNS metastases and glioma separately. The rating of each item did not differ significantly between the two subtypes of brain tumors (data not shown). Their combined overall reporting quality scores also did not differ significantly from each other (F = 0.02; P = .96).


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  		Table 2. Overall Quality of Reporting: Ratings Using Items From the CONSORT Statement

 
For the rating of key methodologic factors, the {kappa} was 0.82 (95% CI, 0.79 to 0.88) for allocation concealment, 0.88 (95% CI, 0.85 to 0.91) for blinding, and 0.90 (95% CI, 0.87 to 0.93) for ITT. When we considered the entire cohort of RCTs, less than 30% of them scored positive in each factor (Table 3). Similar to overall reporting, the scores for each factor and the combined scores did not differ significantly between CNS metastases and glioma (F = 0.47; P = .49). Therefore, all additional analyses involving overall and key methodologic reporting qualities combined the 74 RCTs.


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  		Table 3. Overall Quality of Reporting: Reporting Quality of Key Methodologic Factors

 
Among those trials that described allocation concealment, the most common method was centralized randomization (Table 4). Blinding of the treating physicians, patients, or outcome assessors was uncommon, even though it could have been accomplished in at least one group in more than 62% of RCTs (Table 5). More than two thirds of RCTs did not mention whether there was any loss to follow-up and did not describe ways of handling missing outcomes (Table 6); about half of all trials excluded patients who were falsely included, most often due to wrong neuropathologic diagnoses.


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  		Table 4. Overall Quality of Reporting: Methods Used to Ensure Allocation Concealment

 

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  		Table 5. Overall Quality of Reporting: Blinding Rates by Groups Involved in RCTs

 

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  		Table 6. Overall Quality of Reporting: Specific Applications of ITT

 
Figure 2 shows a gradual improvement in overall reporting quality every 5 years, but the greatest progress in scores was from the period 1990 to 1994 compared with 1995 to 1999. Table 7 lists the distribution of 74 brain tumor RCTs by the reporting of key methodologies and overall quality reporting scores, which were divided into quartiles. Only 41.7%, 20.8%, and 45.8% of RCTs in the top quartile of overall quality scores described allocation concealment, mentioned blinding, and performed ITT analyses, respectively. Therefore, good overall reporting does not invariably guarantee the reporting of the most important methodologic qualities that safeguard against bias.


Figure 2
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  		Fig 2. The distribution of overall quality rating scores during the year intervals studied.

 

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  		Table 7. Distribution of 74 RCTs by the Reporting of Key Methodologies and Overall Quality Reporting Scores

 
Factors Associated With Reporting Quality
Tables 8 and 9 list the univariate analyses of factors associated with overall quality reporting scores and each category's median score. The final multivariable regression model shows that impact factor above 1.660, publication after 1995, and sample size more than 280 were significantly associated with better overall reporting quality (Table 10).


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  		Table 8. Univariate Analyses and Median Scores of Factors Associated With Overall Reporting Quality

 

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  		Table 9. Univariate Analyses and Median Scores of Factors Associated With the Reporting of Key Methodologies

 

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  		Table 10. Multivariable Regression Models Showing Predictors of Overall Reporting Quality and Key Methodologic Factors Reporting

 
A somewhat different set of factors was associated with the reporting of key methodologic factors (Table 9). The highly significant category described as completely funded by industries remained significant (incidence rate ratio, 2.42; 95% CI, 1.57 to 3.73; P < .0001) when the analysis excluded trials that did not report funding. In the final multivariable regression model (Table 10), RCTs completely funded by industries, trials with positive primary outcome, and impact factor of published journal greater than 2.636 remained significant predictors; the impact factor category more than 4.284 was borderline significant. The R2MARG for the regression model of overall reporting quality was 0.57, which means 57% of the variance in the outcome was explained by the model. Similarly, the R2MARG for the model of key methodologic reporting was 0.62.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
Appendix
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
This assessment of reporting quality of brain tumor RCTs showed general improvement during a span of 15 years. Some specific areas, such as allocation concealment, blinding, analysis according to the ITT principle, and details of the randomization scheme, were still poorly reported even in recent years. These findings seem to support the impression that it may be easier for authors to describe clinical features of their studies, such as the inclusion criteria and therapeutic regimens, than to report trial methodology and statistical features.17 An awareness of the importance of these features may help; one study showed that RCTs published by principle investigators with epidemiology affiliations scored significantly higher on reporting quality.18

To our knowledge, there is one other assessment of randomized trials in the primary treatment of an entire oncology subspecialty (breast oncology), but it was published before the establishment of guidelines.19 The most common deficiencies identified in that study, such as descriptions related to the randomization process, allocation concealment, and the handling of withdrawals (part of ITT), were also shortcomings found in this appraisal. Although our assessment was conducted nearly 20 years later, the reporting of these essential methodologies does not seem to have changed.

The finding that factors predictive of key methodologic qualities were different from those associated with overall reporting quality is intriguing. RCTs with positive outcomes may reflect an increased effort into the reporting of important methodologic features to minimize the scrutiny of biases, given that studies that excluded patients after random assignment or did not report allocation concealment yield more positive results.9 Similarly, better reporting associated with complete industrial funding may arise from the desire of sponsors to alleviate the concern that trials funded exclusively by pharmaceutical companies may result in biased findings. This view is supported by another investigation, which found that trials supported solely by profit-making organizations had a trend toward higher quality scores.20 Nevertheless, this significant factor needs to be interpreted with caution, given that there were only five RCTs completely financed by industrial sponsors, and the funding of almost 30% of trials was unknown. Our results remain to be validated in the future when there are more available studies.

Although high journal impact factor is associated with better reporting, it may act as a surrogate for some other characteristics that have a more immediate effect on quality. It is a measure of a journal's prestige, and more influential journals may have more rigorous peer-review processes and attract the submission of better quality papers. Given that many brain tumor therapies are expected to have small benefit, large sample size may be a proxy for meticulous trial planning, which in turn may correlate with better reporting.

One limitation of this study is that we cannot verify trial methodology reported in these articles. In fact, the degree to which reporting quality reflects true methodologic quality of an RCT is the subject of continuous debate. Two studies support the idea that bad reporting does not mean bad methodology. The first study was conducted by the Radiation Therapy Oncology Group on a selection of 56 of the consortium's RCTs.21 They found that many aspects of trial methodology not reported in the final articles were stated in the protocols. If this finding is validated in a larger study, the results may apply to the eight Radiation Therapy Oncology Group trials in our cohort. Another study that sampled 35 RCTs from ACP Journal Club, Journal Watch, and Internal Medicine Alert compared published reports with data provided directly by the authors; the results suggested that blinding and allocation concealment were under-reported but were often conducted.22 However, two investigations furnished contradictory evidence. One study that correlated published randomized trials conducted in Denmark between 1994 and 1995 and their protocols found that many trials with unclear allocation concealment in the article also had an unclear description in the protocols.23 In another survey that examined 63 RCTs of breast cancer treatment, data from the published reports were compared with information provided by the principle investigators; the conclusion was that deficient reporting did reflect flawed methods.19 Small sample size, the reliability of surveyed investigators, variation in the quality of sampled journals, and the number of nonresponders may account for discrepancies of these methodologic studies. In the future, the availability of all RCT protocols in the public domains may help to facilitate the assessment of trial methodology.24

This study has other limitations. The appraisal of reporting quality was limited to those aspects related to the study design and analysis; we have chosen not to assess the quality of discussion and the validity of authors' conclusions because previous evaluations found that these assessments were too subjective, with poor correlations between raters.25 Furthermore, our assessment offers no insight into the ratings of other aspects of clinical trial methodology, such as the external validity and appropriateness of the comparison arm, because they are not part of CONSORT and have not been validated extensively in other scales.

The inclusion of all brain tumor histology in a wide range of journals and the coverage of a relatively long period of time do allow substantial generalization of our quality ratings. This first survey, therefore, represents one of the initial steps toward improving evidence-based practice in neuro-oncology; in the future, we suggest that all RCTs of brain tumor therapies should report the methodologic items outlined in the revised CONSORT statement, especially those pertaining to allocation concealment, blinding, and ITT.


   Appendix
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix
Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
The following RCTs were included in this study (in alphabetical order by the first author):

  1. Cisplatin does not enhance the effect of radiation therapy in malignant gliomas: EORTC Brain Tumor Group. Eur J Cancer 27:568-571, 1991
  2. Medical Research Council Brain Tumor Working Party: Randomized trial of procarbazine, lomustine, and vincristine in the adjuvant treatment of high-grade astrocytoma: A Medical Research Council trial. J Clin Oncol 19:509-518, 2001
  3. Andrews DW, Scott CB, Sperduto PW, et al: Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: Phase III results of the RTOG 9508 randomized trial. Lancet 363:1665-1672, 2004
  4. Arriagada R, Le CT, Riviere A, et al: Patterns of failure after prophylactic cranial irradiation in small-cell lung cancer: Analysis of 505 randomized patients. Ann Oncol 13:748-754, 2002
  5. Bleehen NM and Stenning SP: A Medical Research Council trial of two radiotherapy doses in the treatment of grades 3 and 4 astrocytoma: The Medical Research Council Brain Tumor Working Party. Br J Cancer 64:769-774, 1991
  6. Brem H, Mahaley MS Jr, Vick NA, et al: Interstitial chemotherapy with drug polymer implants for the treatment of recurrent gliomas. J Neurosurg 74:441-446, 1991
  7. Buckner JC, Schomberg PJ, McGinnis WL, et al: A phase III study of radiation therapy plus carmustine with or without recombinant interferon-alfa in the treatment of patients with newly diagnosed high-grade glioma. Cancer 92:420-433, 2001
  8. Cannavo S, Squadrito S, Curto L, et al: Effectiveness of slow-release lanreotide in previously operated and untreated patients with GH-secreting pituitary macroadenoma. Horm Metab Res 33:618-624, 2001
  9. Carapella CM, Paggi MG, Calvosa F, et al: Lonidamine in the combined treatment of malignant gliomas: A randomized study. J Neurosurg Sci 34:261-264, 1990
  10. Cho DY, Liau WR: Comparison of endonasal endoscopic surgery and sublabial microsurgery for prolactinomas. Surg Neurol 58:371-375, 2002
  11. De Luis DA, Becerra A, Lahera M, et al: A randomized cross-over study comparing cabergoline and quinagolide in the treatment of hyperprolactinemic patients. J Endocrinol Invest 23:428-434, 2000
  12. Dinapoli RP, Brown LD, Arusell RM, et al: Phase III comparative evaluation of PCNU and carmustine combined with radiation therapy for high-grade glioma. J Clin Oncol 11:1316-1321, 1993
  13. Elliott TE, Dinapoli RP, O'Fallon JR, et al: Randomized trial of radiation therapy (RT) plus dibromodulcitol (DBD) versus RT plus BCNU in high grade astrocytoma. J Neurooncol 33:239-250, 1997
  14. Eyre HJ, Crowley JJ, Townsend JJ, et al: A randomized trial of radiotherapy versus radiotherapy plus CCNU for incompletely resected low-grade gliomas: A Southwest Oncology Group study. J Neurosurg 78:909-914, 1993
  15. Farkkila M, Jaaskelainen J, Kallio M, et al: Randomized, controlled study of intratumoral recombinant gamma-interferon treatment in newly diagnosed glioblastoma. Br J Cancer 70:138-141, 1994
  16. Glantz MJ, Jaeckle KA, Chamberlain MC, et al: A randomized controlled trial comparing intrathecal sustained-release cytarabine (DepoCyt) to intrathecal methotrexate in patients with neoplastic meningitis from solid tumors. Clin Cancer Res 5:3394-3402, 1999
  17. Gregor A, Cull A, Stephens RJ, et al: Prophylactic cranial irradiation is indicated following complete response to induction therapy in small cell lung cancer: results of a multicenter randomized trial—United Kingdom Coordinating Committee for Cancer Research (UKCCCR) and the European Organization for Research and Treatment of Cancer (EORTC). Eur J Cancer 33:1752-1758, 1997
  18. Grossman SA, O'Neill A, Grunnet M, et al: phase III study comparing three cycles of infusional carmustine and cisplatin followed by radiation therapy with radiation therapy and concurrent carmustine in patients with newly diagnosed supratentorial glioblastoma multiforme: Eastern Cooperative Oncology Group Trial 2394. J Clin Oncol 21:1485-1491, 2003
  19. Guerrieri M, Wong K, Ryan G, et al: A randomized phase III study of palliative radiation with concomitant carboplatin for brain metastases from nonsmall cell carcinoma of the lung. Lung Cancer 46:107-111, 2004
  20. Haie-Meder C, Pellae-Cosset B, Laplanche A, et al: Results of a randomized clinical trial comparing two radiation schedules in the palliative treatment of brain metastases. Radiother Oncol 26:111-116, 1993
  21. Halperin EC, Gaspar L, Imperato J, et al: An analysis of radiotherapy data from the CNS Cancer Consortium's randomized prospective trial comparing AZQ to BCNU in the treatment of patients with primary malignant brain tumors: The CNS Cancer Consortium. Am J Clin Oncol 16:277-283, 1993
  22. Halperin EC, Herndon J, Schold SC, et al: A phase III randomized prospective trial of external beam radiotherapy, mitomycin C, carmustine, and 6-mercaptopurine for the treatment of adults with anaplastic glioma of the brain: CNS Cancer Consortium. Int J Radiat Oncol Biol Phys 34:793-802, 1996
  23. Hiesiger EM, Green SB, Shapiro WR, et al: Results of a randomized trial comparing intra-arterial cisplatin and intravenous PCNU for the treatment of primary brain tumors in adults: Brain Tumor Cooperative Group trial 8420A. J Neurooncol 25:143-154, 1995
  24. Hildebrand J, Sahmoud T, Mignolet F, et al: Adjuvant therapy with dibromodulcitol and BCNU increases survival of adults with malignant gliomas: EORTC Brain Tumor Group. Neurology 44:1479-1483, 1994
  25. Immonen A, Vapalahti M, Tyynela K, et al: AdvHSV-tk gene therapy with intravenous ganciclovir improves survival in human malignant glioma: A randomized, controlled study. Mol Ther 10:967-972, 2004
  26. Iwadate Y, Namba H, Saegusa T, et al: Intra-arterial mannitol infusion in the chemotherapy for malignant brain tumors. J Neurooncol 15:185-193, 1993
  27. Jiang R, Liu Z, Zhu C: Preliminary exploration of the clinical effect of bleomycin on craniopharyngiomas. Stereotact Funct Neurosurg 78:84-94, 2002
  28. Karim AB, Maat B, Hatlevoll R, et al: A randomized trial on dose-response in radiation therapy of low-grade cerebral glioma: European Organization for Research and Treatment of Cancer (EORTC) Study 22844. Int J Radiat Oncol Biol Phys 36:549-556, 1996
  29. Karim AB, Afra D, Cornu P, et al: Randomized trial on the efficacy of radiotherapy for cerebral low-grade glioma in the adult: European Organization for Research and Treatment of Cancer Study 22845 with the Medical Research Council study BRO4—An interim analysis. Int J Radiat Oncol Biol Phys 52:316-324, 2002
  30. Knerich R, Adinolfi D, Giunta F, et al: Single versus multiple drug therapy in the combined treatment of malignant gliomas: A multicenter study. J Neurosurg Sci 34:251-255, 1990
  31. Kochii M, Kitamura I, Goto T, et al: Randomized comparison of intra-arterial versus intravenous infusion of ACNU for newly diagnosed patients with glioblastoma. J Neurooncol 49:63-70, 2000
  32. Komarnicky LT, Phillips TL, Martz K, et al: A randomized phase III protocol for the evaluation of misonidazole combined with radiation in the treatment of patients with brain metastases (RTOG-7916). Int J Radiat Oncol Biol Phys 20:53-58, 1991
  33. Kondziolka D, Patel A, Lunsford LD, et al: Stereotactic radiosurgery plus whole brain radiotherapy versus radiotherapy alone for patients with multiple brain metastases. Int J Radiat Oncol Biol Phys 45:427-434, 1999
  34. Lamberts SW, Quik RF: A comparison of the efficacy and safety of pergolide and bromocriptine in the treatment of hyperprolactinemia. J Clin Endocrinol Metab 72:635-641, 1991
  35. Laperriere NJ, Leung PM, McKenzie S, et al: Randomized study of brachytherapy in the initial management of patients with malignant astrocytoma. Int J Radiat Oncol Biol Phys 41:1005-1011, 1998
  36. Laplanche A, Monnet I, Santos-Miranda JA, et al: Controlled clinical trial of prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Lung Cancer 21:193-201, 1998
  37. Levin VA, Uhm JH, Jaeckle KA, et al: Phase III randomized study of postradiotherapy chemotherapy with alpha-difluoromethylornithine-procarbazine, N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosurea, vincristine (DFMO-PCV) versus PCV for glioblastoma multiforme. Clin Cancer Res 6:3878-3884, 2000
  38. Levin VA, Hess KR, Choucair A, et al: phase III randomized study of postradiotherapy chemotherapy with combination alpha-difluoromethylornithine-PCV versus PCV for anaplastic gliomas. Clin Cancer Res 9:981-990, 2003
  39. Lissoni P, Meregalli S, Fossati V, et al: Radioendocrine therapy of brain tumors with the long acting opioid antagonist naltrexone in association with radiotherapy. Tumori 79:198-201, 1993
  40. Lissoni P, Barni S, Ardizzoia A, et al: A randomized study with the pineal hormone melatonin versus supportive care alone in patients with brain metastases due to solid neoplasms. Cancer 73:699-701, 1994
  41. Lissoni P, Meregalli S, Nosetto L, et al: Increased survival time in brain glioblastomas by a radioneuroendocrine strategy with radiotherapy plus melatonin compared to radiotherapy alone. Oncology 53:43-46, 1996
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   Authors' Disclosures of Potential Conflicts of Interest
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix
 Authors' Disclosures of...
Author Contributions
 REFERENCES
 
The authors indicated no potential conflicts of interest.


   Author Contributions
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix
 Authors' Disclosures of...
 Author Contributions
REFERENCES
 

Conception and design: Rose Lai, Lehana Thabane

Administrative support: Lehana Thabane

Collection and assembly of data: Rose Lai, Rong Chu, Michael Fraumeni

Data analysis and interpretation: Rose Lai

Manuscript writing: Rose Lai

Final approval of manuscript: Rose Lai, Rong Chu, Michael Fraumeni, Lehana Thabane

 


   NOTES
 
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Appendix
 Authors' Disclosures of...
 Author Contributions
 REFERENCES
 
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Submitted June 15, 2005; accepted December 14, 2005.


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