Biopsy vs. extensive resection for first recurrence of glioblastoma: is a prospective clinical trial warranted?

Background Glioblastoma is an aggressive and almost universally fatal tumor. The prognosis at the time of recurrence has generally been poor, with overall survival typically in the range of 4–40 weeks. The merits of surgical resection (vs. open biopsy, to confirm recurrence via histology) in addition to conventional adjuvant chemotherapy have been the subject of longstanding debate. We wondered whether it would possible to conduct a trial at our institution to settle this question definitively with Class I evidence. Results Initially, we had hoped to conduct a randomized, unblinded prospective clinical trial. However on closer inspection it appeared that such an undertaking would pose significant practical challenges. Thus we present our protocol in draft form. In keeping with recommended outcomes for these tumors, the primary endpoint would be median progression free survival. Secondary end points would be: median overall survival (mOS, from time of recurrence) and change in Karnofsky Performance Status over time. Patients would be eligible at the time of first recurrence if they had received conventional treatment until that point and at least 1 month had elapsed since the time of radiation. All patients would be considered potentially eligible for enrollment (unless the decision regarding resection was already clear-cut in view of other factors). Using Cox’s proportional hazards model, we estimate that at least 456 patients would be necessary to demonstrate an increase in the hazard ratio to 1.3 for those undergoing biopsy alone. This magnitude of benefit is estimated based on a review of retrospective studies. Discussion If restricted to our Institution alone, which sees approximately 100–150 new cases of glioblastoma each year, a trial of this nature would be likely to take around 10 years. Furthermore, there may be significant reluctance on the part of patients and physicians to participate. There is also the opportunity cost of excluding patients from other trials to consider. We recognize that the estimate of the magnitude of effect may be conservative. As things stand, we feel that multi-institutional collaboration would almost certainly be required for an undertaking of this kind. Electronic supplementary material The online version of this article (doi:10.1186/s13104-015-1386-3) contains supplementary material, which is available to authorized users.

WNL within normal limits. 20 6 3 Eligibility  The Eligibility Checklist must be completed in its entirety prior to registration. The completed, signed, and dated checklist used at study entry will be retained in the patients study file. 8

Procedure
Patient registration will be conducted in accordance with routine hospital protocol. Enrolled patients will be further registered in a de-identified database maintained by the Research Nurse. GBM (World Health Organization Grade IV astrocytoma), is the most common primary brain tumor in adults and portends a very poor prognosis. [1] Its incidence is estimated to be 3.2/100,000 in the United States. [2] Standard therapy for patients with newly diagnosed GBM usually involves maximal surgical resection, followed by RT (typically 60 Gray, given in 30 fractions) with concomitant and adjuvant temozolomide (TMZ) for at least 6 months. The addition of TMZ to RT has increased median overall survival (mOS) from 12.1 months to 14.6 months, and 2-year survival from 10% to 26%. [4] Recurrence of GBM is almost inevitable. A meta-analysis of 8 Phase II studies involving 225 patients with recurrent GBM, mOS after disease recurrence was 25 weeks and the progression free survival at 6 months (PFS-6) was 15%. [5] Accurately diagnosing recurrence remains a challenge. Pseudo-progression occurs on follow-up imaging in 20-30% of patients imaged at 2 months when treated with standard adjuvant RT and TMZ. [3]. In order to differentiate tumor recurrence from radiographic pseudo-progression, a surgical specimen remains the gold standard.

Surgery
In some cases surgery is essential in order to relieve mass effect caused by tumor growth. However in most cases, once recurrence of tumor has been confirmed (typically by frozen-section performed at the time of surgery), surgery proceeds with the goal of removal of as much of the remaining tumor as possible.
There has been considerable debate about the merits of such a strategy. This is reflected, for example, in the Canadian recommendations for the treatment of recurrent or progressive GBM, which states In the absence of level 1 evidence, the decision to re-operate should be made according to individual circumstances, in consultation with the multidisciplinary team and the patient. [6] By contrast the National Comprehensive Cancer Network guideline for recurrent (local) GBM favors resection when possible. [7] A recent review of literature on the subject, the most comprehensive to date (evaluating 11 studies), concluded that there is no established role for surgery in this setting. [8] Age and KPS were identified as generally important prognostic predictors and to a lesser extent, size of tumor.

Bevacizumab
Regardless of the decision on whether to proceed with surgery (of whatever extent), some form of additional chemotherapy at recurrence is generally agreed to be worthwhile where possible. Although no one agent has yet been endorsed by existing guidelines, all of them give prime consideration of bevacizumab.
Although no phase III trial has been performed to validate this strategy, it has been approved by the Food and Drug Administration (FDA) on the basis of two phase II studies, both published in 2009. In that by Friedman et al., those using bevacizumab alone had a PFS-6 of 43% and mOS of 40 (95% CI 35.6-46.5) weeks. [9] That by Kresyl et al. showed a mOS of 31 (95%CI 21-54) weeks. PFS-6 was 57% (95%CI 44-75). [12] This was a favorable outcome with respect to historical controls, for example those treated with temozolomide alone. Patients randomized to microsurgical resection will undergo routine, imageguided cytoreduction targeting the contrast-enhancing portion of the lesion on T1-weighted contrast-enhanced MRI. Intraoperative adjuncts, including and not limited to, 5-aminolevulinic acid, intraoperative MRI, and intraoperative mapping techniques, will be included as needed per the primary neurosurgeon. Gliadel R (carmustine) wafers will not be placed.

Biopsy
Patients randomized to open biopsy will under routine, In both treatment arms, patients will be treated post-operatively with bevacizumab. The first treatment will be administered on post-operative day 28.

Dose
Bevacizumab will be administered at a dose of 10 mg/kg every 2 weeks. Doses will be adjusted if there is a >10% change in weight. While every effort will be made to keep bevacizumab infusions exactly 14 days apart, it is acknowledged that occasionally a dose must be given off schedule due to logistical reasons. A window of ± 4 days for bevacizumab dosing is acceptable.

Administration
Bevacizumab will be administered intravenously as per current institutional guidelines, with associated pre-medications where required.

Duration of treatment
Treatment with bevacizumab will continue until progression of disease or significant toxicity occurs. Treatment may be held for >grade 3 toxicities as defined in section 8.5. If the patient does not meet criteria to resume treatment within 28 days of the date of the toxicity, they will be removed from the study treatment.

Description and packaging
Bevacizumab is a humanized IgG1 monoclonal antibody (mAb) that binds all biologically active isoforms of human vascular endothelial growth factor (VEGF) with high affinity. The mAb consists of a human IgG1 framework and the antigen-binding, complementarity-determining regions from the murine anti-VEGF mAb A.4.6.1.16-18. Vials contain bevacizumab with phosphate, trehalose, polysorbate 20, and sterile water for injection.

Administration
Bevacizumab should be administered as a continuous intravenous infusion using a rate regulating device per institutional guidelines. Pre-medications (e.g. ondansetron, diphenhydramine, dexamethasone) will be given as per local guidelines. It should not be administered as an intravenous (IV) push or bolus. The first dose should be given over a minimum of 90 minutes. If no adverse reactions occur, the second dose should be given over 60 minutes. If no adverse reactions occur, subsequent doses can be given over a minimum of 30 minutes. If infusion-related adverse reactions occur, all subsequent infusions should be administered over the shortest period that was well tolerated.

Storage
Vials contain no preservative and are suitable for single use only.

Supply
Bevacizumab is available commercially.

Adverse events (AEs)
For studies with participating centers in the USA and registered with the National Cancer Institute (NCI), this is done through the Cancer Therapy Evaluation Program Adverse Event Reporting System (CTEP-AERS). To facilitate reporting, a list of reported and/or potential AEs associated with an agent is provided by the Comprehensive Adverse Event and Potential Risks list (CAEPR). This uses a uniform presentation of events by body system.
In table 8.5 below, these are shown for bevacizumab. In addition to the comprehensive list, a subset subset of AEs is shown which are protocol specific exceptions to expedited reporting to the NCI via CTEP-AERS. These are the Specific Protocol Exceptions to Expedited Reporting (SPEER). This list is based on a recent Radiation Therapy Oncology Group (RTOG) study involving bevacizumab. [14] AEss listed on the SPEER should be reported expeditiously by investigators to the NCI via CTEP-AERS only if they exceed the grade of the event listed in parentheses after the event.     The following have also been reported with bevacizumab but causality has not been established.

Adverse events reported with bevacizumab
Other adverse events reported with bevacizumab Hold bevacizumab treatment. If the planned duration of full-dose anticoagulation is <2 weeks, bevacizumab should be held until the full-dose anticoagulation period is over.
If the planned duration of full-dose anticoagulation is >2 weeks, bevacizumab may be resumed during the period of full-dose anticoagulation if all of the criteria below are met:

Monitoring
Patients will follow up with their Oncologist at monthly intervals. MRIs will be repeated every 2 months, or more frequently if there are new symptoms or signs concerning for disease progression. KPS will be assessed at each visit.

Treatment at time of progression
At time of subsequent progression, the patient will be re-evaluated at our multidisciplinary conference. Decisions will be individualized but will include the options of further surgery, further RT, a change in chemotherapy, treatment with electrical fields (NovoTTF R ) and Palliative care.

Sample size and power justification
The primary objective of this study is to determine whether extensive resection plus bevacizumab (experimental arm) will improve the overall survival compared to open biopsy plus bevacizumab (control arm). The division into experimental and control arms is somewhat arbitrary as both are established treatements at the time of progression and neither has clearly been shown to be superior. Essentially, this is a Phase III design. The randomization of experimental and control arms is 1 : 1. The null hypothesis is that the median PFS for both arms will be 18 weeks, based on data from two Phase II trials of bevacizumab at time of recurrence. [9][12] The alternative hypothesis is that patients treated with an attempt at complete resection plus bevacizumab will have an improvement in overall survival to 23 weeks (hazard ratio (HR) of 1.3). This is based on a review of existing literature (retrospective series) on this subject, which is detailed in the article describing this trial.
Following the methods of Therneau, we assume that the survival distributions will be exponential. [15] The HR is thus the reciprocal of the ratio of median survival times. We aim for a power of 80% and a significance level of 0.05 (two-sided). This would result in a sample size of 456 (assuming all patients are treated as assigned and followed until to to progression). A typical range of power and sample sizes is illustrated in table 11.1 for the above significance level, following the method of Schoenfeld. [13]  Given the risks associated with overestimating the effect size in the study, which would lead to the study being underpowered, we prefer the more conservative margin of a HR of 1.2. Thus, we aim for for a sample size of 945.
Following a review of cases over the preceding 3 years (2009-2012), we estimate that our institution sees 50-70 cases/year of first recurrence of GBM who had previously received standard of care (the Stupp regimen, i.e. concurrent RT and TMZ followed by adjuvant TMZ). [4] This numers seen appear to be stable over this time period. We will include those who were receiving this regimen as part of another trial. We estimate that 60-70% will be eligible for entry, and agreeable, to participation in the study, giving approximately 40 entrants/year.
Given the more optimistic threshold of a HR of 1.3, the trial would take 11 years to accrue. With the more conservative HR of 1.2, the trial would need to run for c. 23 years.

Patient accrual
This study is projected to accrue 3-4 patients/month. If the average accrual is <2 patients/month (6 months after trial activation), the study will be reevaluated with respect to feasibility.

Patient selection and randomization
All cases will be reviewed at our weekly weekly Multidisciplinary Central Nervous System Tumor Conference. Enrollment will be considered for all patients meeting the eligibility criteria. 3 Patients will be stratified at the time of enrollment; this will be followed by radomization, as shown in the study schema 2.

Analysis plans
In general, comparisons between groups will have a significance (type I error) of p < 0.05 (2-sided).
Progression-free and overall survival rates will be estimated using the Kaplan-Meier method. [11] Differences between treatment arms will be tested with the log-rank test. [10] PFS-6 and mOS will be measured from the date of randomization to the date of death or, otherwise, to the last follow-up date on which the patient was known to be alive.
Proportions/ rates will be modelled using an exact binomial distribution, with 95% confidence intervals. These are: PFS-6, objective response, grade 3+ toxicities and acute or delayed CNS toxicities. For secondary endpoints, no adjustament is planned for multiple comparisons as these are exploratory tests.
MOS and PFS-6 will also be modelled with multivariate analyses using the Cox proportional-hazards model. The planned covariates of interest are: • Protocol treatment (biopsy or extensive resection) • Age • Tumor volume at time of recurrence Number of critical areas of cortex involved (0-3) 13 • Time since original diagnosis The assumption of roportional hazards will be checked using residuals and time-varying coefficients. If the data clearly do not follow proportional hazards, other statistical models will be used to fit the data instead. Possible alternatives are to use the stratified Cox proportional hazard model, accelerated failure model, or to partition the time axis into sections where proportional hazards assumption holds.

Interim toxicity and futility analysis
Interim analysis will be undertaken on an annual basis following the methods of O'Brien and Fleming. [16] The study will be terminated of study should these initial results indicate a marked superiority of one treatment over the other. 13 These are

Significance Testing for Final Analysis
The final analysis will be performed on an intention-to-treat basis, such that all eligible cases on the study will be included in the arm to which they were randomized, regardless of what treatment the patients actually received. The analysis to report the final results of treatment comparison between the experimental arm and the control arm will be undertaken once the required sample size has been accrued. If the p value is less than protocol-specified 0.05 (twosided), the study Statistician will reject the null hypothesis and conclude that observing such a dataset would be highly unlikely if the outcome in both arms was really similar. Thus the data would support the hypothesis that the experimental arm improves progression-free survival. The final report will include all information reported in the interim analyses as well as treatment compliance and adverse events.
12 Data collection

Data storage and analysis
The Research Nurse assigned to this study will tabulate, store, and secure data in a single password-protected Excel R database located on a passwordprotected computer in their locked office. Data analysis will be completed by the Principal Investigator and Statistician.

Data safety monitoring plan
The Data Safety Monitoring Plan is written to ensure the safety of the participants and verifying the validity and integrity of the data. All adverse events will be reported to the institutional review board (IRB) and FDA in an expedited manner within 10 days of occurrence. The investigator will continue to follow or obtain documentation of the resolution course of such an event.

Ethical considerations and protection of human subjects
For patients that meet the inclusion criteria, informed consent will be obtained at the time of consent for brain tumor surgery. The option to enter the trial will be presented to the patient, if he/she is able to consent, or to the legal guardian/durable power of attorney in all other circumstances. For all patients, the risks, benefits and alternatives of the trial will be discussed separately from those associated with the planned operation. Refusal to participate in the trial will not affect management strategies or therapeutic options.

Potential risks
The risks of study inclusion are similar to the risks of open neurosurgical tumor resection. This includes, but is not limited to, death, coma, infection, blood loss, and permanent neurological deficit.

Potential benefits
While the study provides no direct benefit to the patient, its findings may clarify the value of greater extent of resection for patients with recurrent glioblastoma.

What other alternatives are there?
If you decide not to participate in this research study, this will not affect the care to which you are entitled and will not influence your doctor in any way. If you decide not to participate, your doctor will discuss alternative treatment options with you. Some of these options may include open surgery, open biopsy, needle biopsy, and observation.

Protecting confidentiality
Each consented participant will be assigned a study identification number. All data will be collected and stored under this identification number, with no other identifying information such as name, date of birth, or social security number. All collected data will be kept on premises of the Hospital in a passwordprotected desktop computer located in a locked office accessible only to the Principal Investigator and Study Co-ordinator. A list of corresponding medical record numbers will be similarly tabulated and protected.

Costs
There will be no additional supply or equipment costs incurred to the patient or the hospital by this study. All proposed therapies are within the acceptable standards of current care options and will be billed to the patients insurance company, as would otherwise be the case.

A Sample consent form
Why am I being asked to participate in this research study?
You have been identified as a possible candidate for participation in a clinical research study called 'Biopsy vs Extensive Resection for first recurrence of Glioblastoma: The BERG trial'. A research study is performed when physicians try find new ways to diagnose and/or treat illness. Since this research study is experimental and the anticipated results have not been proven, you need to know enough about the risks and benefits to decide if you want to participate. This process is called informed consent.
The Research Nurse working with the Principal Investigator for this research study, will discuss this study with you in detail. This Informed Consent document explains what will be expected of you and what risks or benefits you may anticipate if you agree to participate. You should read this document very carefully and ask as many questions as you need to fully understand what your involvement in this study means. Please understand that by signing this document you agree to participate in this experimental study.
How many people will take part in this study?
This Hospital is sponsoring this research study. It is being conducted only at this Hospital. A target of a total of 945 patients will participate.

Why is this study being done?
This research study is designed to better understand the value of greater extent of resection when your tumor shows signs of recurrence. By randomizing patients to extensive resection vs. open biopsy, we will determine whether one has more clinical value than the other. This remains an unresolved question. All proposed treatments are already FDA-approved and are not experimental.

What is involved in this study?
If you choose to participate in this study, you will be selected for either open biopsy (where a small hole is made in the skull to take a piece of the abnormal tissue and make a diagnosis) or microsurgical resection (where an opening in the skull is made to expose all the abnormal tissue and remove everything that is safe). These are both currently standard therapy options for patients with your diagnosis. The purpose of the study is to determine which provides more clinical benefit. Following surgery, you will recover as you would normally and then, if the tissue that is removed is diagnosed as recurrent tumor, receive IV bevacizumab, an anti-tumor agent that commonly given to patients at the time of recurrence. Your clinical follow-up after this will be no different than it would be otherwise, with routine appointments to see your Neuro-Oncologist and Neurosurgeon at regular intervals.
How long will I be on the study?
If you agree to take part in this study, we will continue up with you for at least 3 years. As stated above, no additional appointments will be needed during this time.
What are the risks of this study?
The risks of this study are similar to those that you would be faced with during routine management of your tumor.
Risks associated with brain surgery, include death, neurological problems such as weakness, difficulty seeing or using language, blood loss, and infection.
Risks associated with bevacizumab include wound infection, hematological abnormalities (low blood counts), and gastrointestinal problems.
Are there benefits to taking part in this study?
This study involves treatments which would be available to you outside the context of the study. However there may be benefits either to having a surgical resection or to having a biopsy alone in terms of quality of life and survival. Also, the knowledge gained from this study may benefit others in the future.

What other options are there?
If you decide not to participate in this research study, this will not affect the care to which you are entitled and will not influence your doctor in any way. If you decide not to participate, your doctor will discuss alternative treatment options with you. Some of these options may include open surgery, open biopsy, needle biopsy, and observation.

How will I be informed of additional information or new findings?
If you decide to participate, your doctor will keep you informed of any new findings that are discovered during the course of this study which may affect your continued willingness to participate in this study.

What about confidentiality?
Every attempt will be made to keep your participation in this research study and your records confidential. However, representatives from the Department of Health and Human Services (DHHS), from the FDA and the Hospital may inspect your research records to evaluate the results of this study. The results of this research study may also be published in scientific journals and/or may be presented at scientific meetings, but your identity will not be revealed.
A description of this clinical trial will be made available on ClinicalTrials.gov, as is required by U.S. Law. This Web site will not include information that can identify you. At most, the Web site will include a summary of the results. You can search this Web site at any time.
What are the costs?
There are no additional costs for you that are associated with this trial. As always, you understand that you will be responsible for payment of any bills that your insurance may refuse to pay due to your participation in this research study.
What happens if I am injured while participating in the study?
If you experience an injury or adverse event, please contact the Principal Investigator at 123 456 78910. If the investigator determines that the injury or adverse event is due to your participation in this research, this will be treated, although you are always responsible for the financial costs associated with your care. This does not waive your rights in the event of negligence.

What are my rights as a participant?
You understand that your participation in this research study is voluntary and that you are free to withdraw from this study at any time. If you decide not to participate, your doctor will not hold it against you in any way. If you decide to withdraw from this study at a later date, please notify the Principal Investigator of your decision and to discuss your alternative treatment options.
You understand that your doctor may also stop your participation on this study if it is felt to be in the best interest of your health. This may be done without your consent, but alternative treatment options will be discussed with you.

Whom do I call if I have questions?
If you have any questions about this research study or your participation in it, please feel free to ask them now. If you think of questions later or have concerns about your participation, please call the Principal Investigator at 123 456 78910.
If you have any questions about your rights as a research subject or about the Institutional Review Board for Human Research (IRB) at the Hospital. The board has reviewed this Informed Consent document for compliance with federal guidelines. They may be contacted at: Institutional Review Board Hospital Address Phone no. You are voluntarily deciding whether or not to participate in the research study described in this consent form. Your signature below indicates that you have read and understand the information provided, and that you have decided to participate. You will receive a copy of the signed informed consent document.