Intra-arterial chemotherapy for high-grade gliomas

  • Protocol
  • Intervention

Authors

  • Xian Tao Zeng,

    1. Taihe Hospital, Hubei University of Medicine, Department of Stomatology, Shiyan, Hubei, China
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  • Wei Jing Bi,

    Corresponding author
    1. Sichuan University, The Department of Head, Neck and Breast Oncology, Cancer Center, West China Hospital; The State Key Laboratory of Biotherapy, Chengdu, Sichuan, China
    • Wei Jing Bi, The Department of Head, Neck and Breast Oncology, Cancer Center, West China Hospital; The State Key Laboratory of Biotherapy, Sichuan University, Wai Nan Guo Xue Line, No.37, Chengdu, Sichuan, 610041, China. fairybluebird@163.com. 175509797@qq.com.

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  • Ping Li,

    1. Sichuan University, The Department of Head, Neck and Breast Oncology, Cancer Center, West China Hospital; The State Key Laboratory of Biotherapy, Chengdu, Sichuan, China
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  • Ai Ping Deng,

    1. Taihe Hospital, Hubei University of Medicine, Department of Neurosurgery, Shiyan, Hubei, China
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  • Li Zhang,

    1. Taihe Hospital, Hubei University of Medicine, Department of Neurosurgery, Shiyan, Hubei, China
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  • Yan Chu Li,

    1. Sichuan University, The Department of Head, Neck and Breast Oncology, Cancer Center, West China Hospital; The State Key Laboratory of Biotherapy, Chengdu, Sichuan, China
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  • Zhiyong Dong

    1. The First Affiliated Hospital of Guangxi Medical University, Hepato-Pancreato-Biliary Surgery, Nanning, Guangxi, China
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Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To evaluate the effects and safety of intra-arterial chemotherapy in children and adults with high-grade gliomas, compared with conventional therapies.

Background

Description of the condition

Intracerebral tumours (tumours that arise within the brain) attract significant research interest due to their poor prognosis. These tumours are graded on a scale from I to IV as defined by the World Health Organisation (WHO) classification of tumors of the central nervous system (CNS), which is based on a malignancy scale and proliferative potential of the tumour (Kleihues 1993; Louis 2007), i.e. how fast they grow and how likely they are to spread.

When intracerebral tumours develop from the supporting tissue of the brain (glial cells), they are known as gliomas. Gliomas may be of different grades of severity, ranging from very slow growing grade 1 tumours to more aggressive grade 3 (anaplastic) or grade 4 (glioblastoma) tumours. Grade 1 and grade 2 tumours are known as low-grade gliomas (LGGs) whereas grade 3 and 4 - the most aggressive and infiltrating types - are known as high-grade gliomas (HGGs), or malignant gliomas. Malignant or HGGs are perceived as incurable, with a median survival following surgical resection alone of approximately three months (Davis 1998). They are characterised by the presence of necrosis, are highly proliferative and invasive, and infiltrate without definite boundary. Common clinical symptoms include a mixture of headache, focal neurological deficits, epileptic seizures, altered mental state and gait dysfunction (Bredel 1997; Croteau 2001; Reddy 2003; Grant 2004; Rooney 2011).

There are three main types of HGGs, which are named according to the cell types they resemble:

  • ependymomas, which develop from ependymal cells which line the cavities in the brain;

  • oligodendrogliomas, that arise from oligodendrocytes, which produce fatty coverings to insulate the nerves and are usually found in the temporal or frontal lobes; and

  • astrocytomas, developing from star-shaped cells, astrocytes, which perform a variety of functions relating to supporting the biochemical composition of the fluid which acts as a nutrient to neurons and endothelial cells that forms the blood brain barrier and formation of the brain's framework.

The majority of HGGs are anaplastic oligodendrocytomas (AO) and astrocytomas (glioblastoma multiforme (GBM), anaplastic astrocytoma (AA)).

Each year, there are 6 to 8 new cases of glioma per 100,000 population and for GBM approximately 3 to 4 per 100,000 in the USA (Christensen 2011); 8 per 100,000 in the UK (Counsell 1996); and 200 cases per year in Norway (Storstein 2011). The peak age of onset is between 50 and 60 years. Epidemiological surveys show that survival rates at 2, 3, 4 and 5 years after diagnosis are 27.3%, 16.7%,12.9% and 6.1%, respectively ( Stupp 2005; Storstein 2011).

Description of the intervention

Up to now, there is no treatment approach to cure gliomas. Currently, the recommended treatment option is surgery (biopsy or resection) followed by radiation therapy alone or in combination with chemotherapy (Desjardins 2005; Stupp 2005). Conventional chemotherapeutic agents are given intravenously or orally at relatively high dosage. Some practitioners have hypothesised that the unsatisfactory outcomes and frequent systemic adverse effects associated with these agents could be avoided by the use of intra-arterial chemotherapy (the administration of chemotherapeutic drugs by injection into the artery supplying the tumour) (Emerich 2000; Neyns 2010).

Research has shown that intra-arterial chemotherapy was able to deliver localised and elevated concentration of chemotherapeutic agents within the tumour site, and thus lower systemic exposure (Shapiro 1992; Hiesiger 1995; Imbesi 2006). However, the risk of local adverse effects from carotid artery infusion of chemotherapy, such as optic nerve neuropathy, local pain in the carotid distribution, and focal encephalopathy, remains unknown.

How the intervention might work

The major arteries supplying the front of the brain are the carotid arteries, while the back of the brain is supplied by the vertebral arteries and basilar arteries. There are two carotid arteries, one on each side of the neck.  If a tumour is confined to one side of the front part of the brain, the tumour's blood supply generally comes from only one of the carotid arteries. Chemotherapy drugs given into the carotid artery (intra-arterial chemotherapy) can be given at a lower dose than would be required if they were given by oral route or into the vein. The concentration of chemotherapy reaching the glioma will be the same or possibly higher than if it were given by oral or intravenous routes (Basso 2002; Newton 2005). As a result, the side effect profile of intra-arterial chemotherapy is different, with more common local side effects due to local damage to the artery or to the organs supplied by that carotid artery on that side of the brain or the eye on the same side.  In some cases it is possible to deliver the chemotherapy beyond the level at which the artery to the eye leaves the carotid artery (supra carotid injection) in an attempt to minimise toxicity to the eye. The side effects must be balanced against the toxicity of other chemotherapy routes, which include bone marrow disturbances, and lung or neurological effects from temozolomide, nitrosourea, procarbazine, vincristine or platinum drugs, and which tend to be related to the total dose given.

Why it is important to do this review

There is uncertainty about the role of intra-arterial chemotherapy in treating HGG and if this route of administration is superior to conventional routes in terms of patients' tolerance and adverse effects.We feel that a systematic review to answer these clinical questions is warranted. A previous review observed there was no survival advantage of intra-arterial chemotherapy over intravenous drug delivery. The incidence of serious neurotoxicity was reduced, but the risk of acute complications still contraindicated wider use outside the setting of a clinical trial (Basso 2002).

We aim to determine if intra-arterial chemotherapy is better than conventional treatments and to establish if increased local drug concentration can translate into a clinical advantage, or increases local eye and central nervous system complications.

Objectives

To evaluate the effects and safety of intra-arterial chemotherapy in children and adults with high-grade gliomas, compared with conventional therapies.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) and quasi-RCTs (randomisation based on possible identifiers such as date of birth, hospital number or day of the week).

Types of participants

  • Primary therapy: Patients of all ages with a histologically-confirmed diagnosis of high-grade glioma (HGG) grades Ⅲ or Ⅳ as defined by WHO classification, based on histologic features.

  • Therapy for recurrent disease: Patients of all ages with a previous histologically-confirmed case of HGG and who are diagnosed with recurrent disease.

Types of interventions

  • Interventions: surgery plus radiotherapy plus intra-arterial chemotherapy from any site e.g. common or internal carotid artery, carotid branches, vertebral and basilar arteries, and vertebral-basilar branches.

    • Primary treatment - intra-arterial chemotherapy given after surgical treatment, and shortly after radiotherapy (i.e. combination of surgery, radiotherapy and chemotherapy).

    • Treatment at relapse – intra-arterial treatment given after primary treatment has failed and tumour has recurred (chemotherapy alone at relapse).

  • Comparators: surgery plus radiotherapy plus chemotherapy via other routes of administration (intravenous or oral).

Types of outcome measures

Primary outcomes
  1. Overall survival (OS), defined as survival until death from all causes. Survival time will be assessed in months from the time when patients are randomised.

Secondary outcomes
  1. Progression-free survival (PFS). Open and thorough criteria should have been used to define recurrence according to clinical symptoms, imaging or increasing steroid therapy (Wen 2010).

  2. Adverse effects which cannot be attributed to the tumour such as headache, dizziness, otitis/ear inflammation, nausea , depressed level of consciousness, seizure, personality change, central nervous system (CNS) necrosis, CNS symptoms not otherwise specified, alopecia, dermatitis, urinary incontinence and more specifically optic nerve neuropathy, local pain in the carotid distribution and focal encephalopathy (CTCAE v4.0).

  3. Quality of life (QoL) as measured using a validated scale.

  4. Time to progression.

  5. Response rate: complete remission plus partial remission as defined by the included trials.

Search methods for identification of studies

We will conduct a comprehensive systematic search to identify all relevant studies regardless of language or publication status.

Electronic searches

We will search:

  • Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, latest issue),

  • MEDLINE (from 1946 to latest issue),

  • EMBASE (from 1980 to latest issue),

  • Chinese Biomedical Literature Database (CBM) (1975 to latest issue),

  • National Research Register (1998 to latest issue),

  • SIGLE (1976 to latest issue).

The MEDLINE search strategy is presented in Appendix 1, and will be adapted for use in other databases.

Searching other resources

Unpublished studies

We will attempt to contact trial authors, relevant pharmaceutical companies and neuro-oncologists who are known to have expertise in using intracerebral chemotherapy in patients with HGG, for information regarding ongoing and unpublished trials.

Handsearching

We will try to identify additional studies by searching the reference lists of all relevant studies, the citations of recent reviews, and conference proceedings. We will also handsearch the last two years of two key neuro-oncology journals (Neuro-Oncology and Journal of Neuro-Oncology), including conference abstracts.

Foreign language studies

The relevant sections of studies not in English or Chinese will be translated if possible.

Data collection and analysis

Selection of studies

Titles and abstracts of all reports identified through the searches will be downloaded to reference management software (EndNote X3), de-duplicated and the remaining references examined by two independent review authors (WJB and PL). We will exclude records which clearly do not meet the inclusion criteria, and obtain full text papers of potentially-relevant references meeting the inclusion criteria or for which there is insufficient information in the title and abstract to make a clear decision. The eligibility of retrieved full texts will be assessed independently by the same two review authors (WJB and PL). Disagreements will be resolved by discussion and if necessary by a third review author (LZ). We will document reasons for exclusion of potentially-relevant papers.

Data extraction and management

Data will extracted by two review authors (XTZ and APD) independently after blinding the source. Data to be extracted include publication data (the first author's last name, year of publication, and country of population studied), sample size, patients' characteristics (mean age and sex ratio), study design, follow-up period, outcome variables and method of measurement. If the data from the trial reports are insufficient or missing, we will contact corresponding authors of the original studies to request missing data.

Assessment of risk of bias in included studies

We will develop a score sheet to assess the risk of bias in each included trial, with trial authors and journal names/titles blinded to two independent review authors (XTZ and WJB) conducting the assessment, in accordance with the Cochrane Handbook guidance for assessing risk of bias (Higgins 2011). We will assess the following criteria:

  1. Sequence generation: was the allocation sequence adequately generated?

  2. Allocation concealment: was allocation adequately concealed?

  3. Blinding: was knowledge of the allocated intervention adequately during the study?

  4. Incomplete outcome data: were incomplete outcome data adequately addressed?

  5. Selective outcome reporting: are reports of the study free of suggestion of selective outcome reporting?

  6. Other sources of bias: was the study apparently free of other problems that could put it at a high risk of bias?

Based on these criteria, studies will be broadly subdivided into the following three categories:

  1. "Yes": low risk of bias;

  2. "Unclear": unclear risk of bias;

  3. "No": high risk of bias.

Agreement between the review authors will be assessed by calculating the kappa score. In case of disagreement, a third review author (PL or YCL) will be consulted and a judgement will be made based on consensus. The results of the meta-analyses will be interpreted in light of the findings with respect to the risk of bias.

Measures of treatment effect

For dichotomous outcomes, we will record the number of patients experiencing the event in each group of the trial, while the arithmetic means and standard deviations will be recorded for continuous outcomes. In case of disagreement, a third review author (LZ) will be consulted.

Results will be extracted as follows:

  • For time to event data (survival and disease progression), we will extract the log of the hazard ratio [log(HR)] and its standard error (SE) from trial reports. If these are not reported, we will attempt to estimate the log(HR) and its SE using the methods of Parmar et al (Parmar 1998) and the HR calculations spreadsheet provided by Tierney et al (Tierney 2007).

  • For dichotomous outcomes (e.g. adverse events or deaths, if it is not possible to use a HR) we will extract the number of patients in each treatment arm who experienced the outcome of interest and the number of patients assessed at endpoint, in order to estimate a risk ratio (RR) with its 95% confidence interval (CI).

  • For continuous outcomes (e.g. quality of life measures), we will extract the final value and standard deviation of the outcome of interest and the number of patients assessed at endpoint in each treatment arm at the end of follow-up, in order to estimate the mean difference (MD) between treatment arms and its 95% CI.

Dealing with missing data

If the data from the trial reports are insufficient or missing, we will contact authors of the original studies to request missing data. An intention-to-treat (ITT) analysis will be conducted where possible, or we will calculate the loss-to-follow-up percentage and report any relevant information if the number of participants randomised and analysed are shown to be inconsistent.

Assessment of heterogeneity

Heterogeneity between trials will be assessed by visual inspection of forest plots, by estimation of the percentage heterogeneity between trials which cannot be ascribed to sampling variation (Higgins 2003), by a formal statistical test of the significance of the heterogeneity (Deeks 2001) and, if possible, by subgroup analyses (see Subgroup analysis and investigation of heterogeneity).  If there is evidence of substantial heterogeneity, the possible reasons for this will be investigated and reported.

The heterogeneity can be divided into four levels according to the I² statistic (Higgins 2011):
• 0% to 40% indicating slight heterogeneity,
• 30% to 60% indicating moderate heterogeneity,
• 50% to 90% indicating substantial heterogeneity,
• 75% to 100% indicating considerable heterogeneity.

Assessment of reporting biases

We will examine funnel plots of the primary outcomes to assess the potential for small study effects such as publication bias. Symmetry of, and outlying results on, the funnel plots would imply lack of bias, whereas asymmetry would imply that the results are subject to reporting or publication bias. If these plots suggest that treatment effects may not be sampled from a symmetric distribution, as assumed by the random-effects model, we will perform further meta-analyses using fixed-effect models.

Data synthesis

If enough clinically-similar studies are available, we will pool their results in meta-analyses.

  1. For time-to-event data, hazard ratios will be pooled using the generic inverse variance.

  2. For dichotomous outcomes, RRs will be calculated and thereafter pooled for overall effect measure data. 

  3. For continuous outcomes, the MDs between the treatment arms at the end of follow-up will be pooled if all trials measured the outcome on the same scale, otherwise we will pool standardised mean differences. 

For trials with multiple treatment groups, the 'shared' comparison group will be divided into the number of treatment groups and comparisons between each treatment group, and the split comparison group will be treated as independent comparisons.

We will use a random0effects model with inverse variance weighting for all meta-analyses (DerSimonian 1986).

If possible, studies making different comparisons will be synthesised using the methods Bucher 1997.

We aim to use the GRADEpro (version 3.2.2, The Cochrane Collaboration) to summarise the findings and rate the overall quality of evidence (GRADEpro 2008).

Subgroup analysis and investigation of heterogeneity

We intend to explore the following potential sources of heterogeneity using subgroup analyses. The following subgroup analyses are proposed:

  1. Different types of cancer (glioblastoma multiforme (GBM), anaplastic astrocytoma, or other types);

  2. Different age groups (children, adults, or the elderly);

  3. Different regimens of chemotherapy;

  4. Different durations of chemotherapy;

  5. Primary or recurrent disease.

Sensitivity analysis

We will explore reasons for heterogeneity in studies and, if necessary, will conduct sensitivity analyses:

  1. Excluding studies at high risk of bias (we define high risk of bias of an RCT as the first three items being rated 'unclear risk' or 'high risk');

  2. Excluding unpublished studies;

  3. Excluding pharmaceutical company-sponsored studies.

Acknowledgements

We thank the Cochrane Gynaecological Cancer and Orphan Cancer Review Group, especially Clare Jess and Jane Hayes for their contributions to the editorial process and search strategy respectively. We thank Prof. Tai Xiang Wu, Prof. Ke Gang Deng, Prof. Guan Jian Liu, and Ms Mao Ling Wei in the Chinese Cochrane Centre; we thank Prof. Yi Guo in the Department of Epidemiology, School of Public Health, Wuhan Unviersity; we also thank Prof. Wei Dong Leng in the Department of Stomatology, Taihe Hospital, Hubei University of Medcine, for their useful suggestions for our protocol.

The National Institute for Health Research (NIHR) is the largest single funder of the Cochrane Gynaecological Cancer Group. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR, NHS or the Department of Health. 

Appendices

Appendix 1. MEDLINE search strategy via Ovid

1. exp Brain Neoplasms/
2. ((brain or intracranial or intra-cranial or intracerebral or intra-cerebral) adj5 (tumour or tumour or neoplasm* or cancer* or malignan* or carcinoma*)).mp.
3. exp Glioma/
4. glioma*.mp.
5. astrocytoma*.mp.
6. oligodendroglioma*.mp.
7. oligoastrocytoma*.mp.
8. glioblastoma*.mp.
9. GBM.mp.
10. ependymoma*.mp.
11. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10
12. drug therapy.fs.
13. exp antineoplastic agents/
14. exp drug administration routes/
15. chemotherap*.mp.
16. (intraarter* or intra-arter* or arter*).mp.
17. 12 or 13 or 14 or 15 or 16
18. 11 and 17
19. randomized controlled trial.pt.
20. controlled clinical trial.pt.
21. randomized.ab.
22. placebo.ab.
23. clinical trials as topic.sh.
24. randomly.ab.
25. trial.ti.
26. 19 or 20 or 21 or 22 or 23 or 24 or 25
27. 18 and 26
28. exp animals/ not humans.sh.
29. 27 not 28

key:
mp=protocol supplementary concept, rare disease supplementary concept, title, original title, abstract, name of substance word, subject heading word, unique identifier
pt=publication type
sh=subject heading
ab=abstract
ti-title
fs-floating subheading

What's new

DateEventDescription
1 April 2015AmendedContact details updated.

History

Protocol first published: Issue 6, 2013

DateEventDescription
27 March 2014AmendedContact details updated.
16 May 2013AmendedFunder details acknowledged

Contributions of authors

WJ Bi conceived the review idea and performed previous work that was the foundation of the current study. WJ Bi, XT Zeng and Z Dong managed the methods of this review. XT Zeng, AP Deng and L Zhang wrote the protocol. P Li and YC Li provided clinical suggestions.

Declarations of interest

None known

Sources of support

Internal sources

  • Hubei University of Medicine, China.

    The Intramural Research Program of the Hubei University of Medcine (2011CZX01)

  • Hubei Ministry of Education, China.

    The Foundation of Education and Science Planning Project of Hubei Province (2012A050)

External sources

  • No sources of support supplied

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