Whole brain radiotherapy with radiosensitizer for brain metastases

Purpose To study the efficacy of whole brain radiotherapy (WBRT) with radiosensitizer in comparison with WBRT alone for patients with brain metastases in terms of overall survival, disease progression, response to treatment and adverse effects of treatment. Methods A meta-analysis of randomized controlled trials (RCT) was performed in order to compare WBRT with radiosensitizer for brain metastases and WBRT alone. The MEDLINE, EMBASE, LILACS, and Cochrane Library databases, in addition to Trial registers, bibliographic databases, and recent issues of relevant journals were researched. Significant reports were reviewed by two reviewers independently. Results A total of 8 RCTs, yielding 2317 patients were analyzed. Pooled results from this 8 RCTs of WBRT with radiosensitizer have not shown a meaningful improvement on overall survival compared to WBRT alone OR = 1.03 (95% CI0.84–1.25, p = 0.77). Also, there was no difference in local brain tumor response OR = 0.8(95% CI 0.5 – 1.03) and brain tumor progression (OR = 1.11, 95% CI 0.9 – 1.3) when the two arms were compared. Conclusion Our data show that WBRT with the following radiosentizers (ionidamine, metronidazole, misonodazole, motexafin gadolinium, BUdr, efaproxiral, thalidomide), have not improved significatively the overall survival, local control and tumor response compared to WBRT alone for brain metastases. However, 2 of them, motexafin- gadolinium and efaproxiral have been shown in recent publications (lung and breast) to have positive action in lung and breast carcinoma brain metastases in association with WBRT.

avoiding unnecessary treatments [3][4][5][6][7][8][9][10][11]. Radiosensitizers are chemical or pharmacologic agents that increase the lethal effects of radiation if administered with it. In an attempt to improve outcomes, studies have examined the use of whole brain radiotherapy combined to radiosensitizers [12][13][14][15][16][17][18]. There are many chemicals capable of rendering cells or tissue more sensitive to radiation, but it only those drugs for which there is a differential response between the tumor and dose-limiting normal tissue that may be of benefit radiotherapy. Dozens of clinical trials have been performed, most of which have been inconclusive or have shown results with a borderline results [19][20][21][22][23][24][25][26][27]. Tsao et al. has presented the results of five randomized controlled trials [5,[19][20][21][22][23]] that examined the use of radiosensitizers in addition to WBRT. However, none of those trials detected a benefit in terms of overall survival or brain response (CR + PR). Moreover, this metaanalysis did not evaluate the incidence of adverse effects, the differences on quality of life or the neurocognitive progression. Since its publication, other studies have been published, investigating new radiosensitizers. So, the aim of our meta-analysis is to evaluate the outcomes and adverse effects of the randomized clinical trials in the treatment of cerebral metastases using radiosensitizer combined to WBRT.

Objectives
The aim of this study is to analyze the efficacy of whole brain radiotherapy plus radiosensitizer compared to whole brain alone for patients with brain metastases in terms of overall survival, disease progression, response to treatment and adverse effects of treatment. Secondary objective was to investigate the treatment effect on neurological status and quality of life.
Criteria for considering studies for this review

Types of studies
All randomised and quasi-randomised controlled trials were eligible for inclusion.

Types of participants
Adult patients were eligible if they had TC or MRI-demonstrated brain metastases from histologically proven solid tumors, required WBRT, with any Karnofsky performance status and RPA class with brain metastases originated from solid tumors, excluding small-cell lung cancer, germ cell tumors, and lymphomas. There were no restrictions regarding gender or nationality. Trials of prophylactic whole brain radiotherapy in which whole brain radiotherapy was used with no evidence of existing brain metastases were excluded. Studies that examined the use of surgery or whole brain radiotherapy, or both, for single brain metastases were also excluded

Types of intervention
All trials were included where adult patients were randomly assigned to receive WBRT given in daily fractions, with or without radiosensitizer.

Types of outcome measures
Data for the following outcome measures were analyzed: The overall survival in six months. Intracranial progression-free duration was defined as the time from randomization or entry to the trial until progressive brain disease is diagnosed. Local brain response was considered as the percentage of patients achieved complete response (CR) or partial response (PR) to treatment. Complete response was defined as complete radiographic disappearance of brain metastases. Partial response was defined as more than 50% decrease in size of the brain metastases on CT or MR imaging. Local brain control was reported to as the percentage of patients with unchanged or improved serial post-treatment CT or MRI scans judged either as a complete response (CR), partial response (PR), or stable disease (SD), with improving or stable neurological symptoms or neurological examination results. SD is defined as a 0 to 50% decrease in size of all lesions with stabilization neurological symptoms or neurological examination results and stable dexamethasone dose. Progressive disease is defined as an increase in the size of any lesion, the development of new lesions, or a decrease in neurological symptoms or examination requiring an increase in dexamethasone dose. Quality of life, symptom control and neurological function assessed by any scale.

Research strategy for identification of studies
Medline and manual research was done (completed independently and in duplicate) to identify all published (manuscripts and abstracts) randomized controlled trials (RCTs) that comparing WBRT plus radiosensitizer treatment for brain metastases to WBRT alone. The Medline research was done on PubMed between 1966 and 2008 with no language restrictions, using the search terms "brain metastases", "radiotherapy" or "metastases," "whole brain radiotherapy" or "radiosensitizer" and "brain radiation." The second research was done through CancerLit, EMBASE, LILACS and the Cochrane Library to identify randomized trials published between January 1998 and July 2007, using MeSH headings (brain metastases, whole brain radiotherapy, radiosensitizer/sc {Sec-ondary}, ex-lode Clinical Trials, clinical trial {publication type}) and text words (brain, cancer, radiotherapy:, radiosensitizer, trial, and study) without language restrictions. All the researched abstracts were screened by relevance. Manual research was done by reviewing articles and abstracts cited in the reference lists of identified RCTs, by reviewing the first author's article, abstract file, from reference lists of retrieved papers, textbooks and review arti-cles. Also, abstracts published in the Proceedings of the Annual Meetings of the American Society of Clinical Oncology were systematically researched for evidence relevant to this meta-analysis. The selection of studies for inclusion was carried out independently by two of the authors (V-GA and S-EJ). Each study was evaluated for quality using the scale of 1 to 5 proposed by Jadad [18]. When reviewers disagreed on the quality scores, discrepancies were identified and a consensus was reached. Trial data abstraction was also done independently and in duplicate, but abstractors were not blinded to the trials' authors or institution. Any discrepancies in data abstraction were examined further and resolved by consensus.

Data analysis
The proportion of patients surviving at six months was treated as dichotomous data. This was estimated from Kaplan-Meier probability curves of survival at six months. For forest plot analyses, mortality data (the inverse of survival at six months) was plotted. An odds ratio (OR) less than 1.0 indicated that the patients in the experimental treatment group experienced fewer deaths compared to those in the control group. Intracranial progression-free duration was defined as the period during which there was no intracranial tumor growth and no new brain metastases. This was treated as continuous data. The heterogeneity of instruments used and the differences in reporting quality of life, symptom control, and adverse effects outcomes were described and not pooled.

Results
The electronic and manual research revealed 2016 entries. These were screened and 38 full text articles were retrieved for further assessment. We excluded 30 studies, as they were either not randomized studies or were not comparisons of medical versus surgical treatment. The reasons for exclusion are detailed in the excluded studies figure 1.
Eight fully published trials [19][20][21][22][23][24][25][26] examined the use of radiosensitizers in addition to whole brain radiotherapy (2217 patients in total). The radiosensitizers used were lonidamide [19] reported specifically on neurocognitive outcomes from the group of patients randomized in the motexafin gadolium trial by Mehta et al [25] reported on the use of whole brain radiotherapy and supplemental oxygen with or without RSR13 (efaproxiral), a novelty in radiation sensitizer that performs as a modifier of hemoglobin to facilitate oxygen release. Table 1 describes the characteristics of the studies included in this meta-analysis.

Setting and participants
The radiosensitizers studied were lonidamide, metronidazole, misonidazole, motexafin gadolinium, bromodeoxyuridine (BrdU), RSR13 (efaproxiral) and thalidomide. In regards to the outcomes of interest, none of the trials reported on either proportion of patients who were able to reduce their daily dexamethasone dose or duration of reduced dexamethasone requirements. All trials used WBRT with total dose range 30 -37.5 Gy in 10-15 fractions.

Overall survival at six months
Seven studies reported overall survival as one of the outcomes. Altogether, the analyses included 7 trials with 1763 patients. The overall mortality rates were not decreased for WBRT with radiosensitizer arm (517/878 = 58.8%) compared to WBRT alone arms (519/885 = 58.6%). The test for heterogeneity was not statistically significant with p value 0.28. The overall odds ratio suggests that there is no difference between WBRT with radiosensitizer arms and WBRT alone arms in terms of overall mortality rate with p value 0.77, as demonstrated in figure 2.

Central nervous system progression
Four studies [19,20,22,25] had reported CNS progression data (three published and one in abstract form), 1099 patients were included in the analysis. There were no more CNS progression in WBRT alone (150/551 = 27.2%) compared to WBRT with radiosensitizer (135/548 = 24.6%). The likelihood of CNS progression was 1.1-fold higher (95% CI 0.8 -1.4) in WBRT arms. Test for heterogeneity was not significant with p value of 0.15, as is in the figure 4. There was also no statistically significant difference between treatment arms in time to neurocognitive progression on the patients treated for whole brain radiotherapy with or without motexafin gadolinium. Patients with lung cancer (but not other types of cancer) who were treated with motexafin gadolinium in addition to whole brain radiotherapy tended to have improved memory and executive function (P value 0.062) and improved neurological function. In the RTOG-0118, quality of life was measured by the SQLI and the Folstein MMSE was used to determine neurocognitive progression. SQLI and MMSE were administered at baseline and at 2-month intervals. MMSE was scored with a threshold value associated with neurocognitive functioning (absolute cutoff level of 23) and with the use of corrections for age and educational level.

Quality of life and the neurocognitive progression
In a secondary analysis of 156 patients neurocognitive and quality of life outcomes were examined and Corn et al.
[27] demonstrated that in spite of the neurocognitive decrease, QOL remained stable during treatment and follow-up, and poor neurocognitive function may predict clinical deterioration.

Adverse effects
All seven published studies that assessed the addition of radiosensitizers to whole brain radiotherapy reported seri-ous adverse effects. In the REACH trial, most of the treatment-emergent adverse effects were grade 1 (mild) to grade 2 (moderate) in severity in both treatment arms. The most commonly reported grade 3 adverse effects in efaproxiral-treated patients were hypoxemia, which was reported in 11% of patients (29 out of 266 patients). In the RTOG 0118 [26], most of the experienced toxicities were not severe but they were significant enough to limit compliance with protocol therapy. The rate of patients experiencing Grade 3-4 treatment-related adverse events on the thalidomide arm (39/84) was significantly higher than the rate on the WBRT arm (11/92) (p < 0.0001). In the SMART trial [24], published by Mehta et al. in abstract form only, most common adverse effects were skin discoloration (66%), urine discoloration (35%), nausea (27%), fatigue (21%) and hypertension (18%). However, grade 3-4 toxicity was very rare 1-4%. DeAngelis et al. [19] found that the most common side effects of lonidamide and WBRT were myalgia (68%), testicular pain (42%), anorexia (26%), ototoxicity (26%), malaise or fatigue (26%), and nausea and vomiting (19%). In the Eyre study [20] it was reported 51% incidence of nausea and vomiting compared to 3.2% in the whole brain radiotherapy arm alone. Komarnicky et al. [19] showed that the administration of the misonidazole with WBRT was well tolerated and produced no grade-three neurotoxicity or ototoxicity. Phillips et al. [22], in the RTOG 8905, reported three fatal toxicities in 34 patients randomized to whole brain radiotherapy with administration of the radi- Overall mortality in the trials included in this meta-analysis comparing WBRT with radisensitizer to WBRT alone Figure 2 Overall mortality in the trials included in this meta-analysis comparing WBRT with radisensitizer to WBRT alone.
Local brain tumor response in the trials included in this meta-analysis comparing WBRT with radiosensitizer to WBRT alone Figure 3 Local brain tumor response in the trials included in this meta-analysis comparing WBRT with radiosensitizer to WBRT alone.
CNS progression in the trial included in this meta-analysis comparing WBRT with radiosensitizer to WBRT alone Figure 4 CNS progression in the trial included in this meta-analysis comparing WBRT with radiosensitizer to WBRT alone.

Discussion
In most patients with brain metastasis, WBRT is the mainstay of treatment and efforts to improve the outcome of WBRT continue. These efforts include radiation sensitizers such as efaproxiral, motexafin gadolinium, and thalidomide.
Historically, chemical modifiers of radiation effect have had little impact on overall average survival times in human trials of brain metastases. Misonidazole, bromodeoxyuridine (BUdR), lonidamine, nimustine, fluorouracil, and others have failed to show significant benefit in randomized trials [19][20][21][22][23][24][25][26]. Recent developments suggest a new interest in this approach with three compounds that show as a promise as radiosensitizers: motexafin gadolinium, thalidomide and efaproxaril.
Efaproxaril is a small, synthetic molecule that non-covalently binds to hemoglobin and decreases its oxygen binding affinity and shifts the oxygen dissociation curve to the left, increasing p50 and tissue pO2. It exerts its effects based on an increase in tumor oxygen levels, thereby circumventing restrictions due to the blood brain barrier [14,28-30] Shaw et al [14] conducted a phase II, openlabel, multicenter study of efaproxaril plus WBRT in 57 patients with brain metastases. The results were retrospectively compared to the RTOG RPA brain metastases database; the average survival time for the efaproxaril treated patients was 6.4 months compared to 4.1 months for the database (P < .0174). Patients with brain metastasis may suffer a certain degree of neurocognitive function (NCF) impairment from multiple factors including the tumor, WBRT, neurosurgical procedures, chemotherapy and other neurotoxic therapies (including anticonvulsants and steroids), or from paraneoplastic effects induced by the malignancy [41].
Three trials included in this meta-analysis evaluated neurocognitive function. However, we were not able to pool these data, due to the different methods used for this outcome. In addition to that, studies involving NCF deterioration should be carefully interpreted. NCF decline in the literature is often defined statistically and there is little consensus as to the actual clinical relevance of a statistical definition. Conventionally, the measures used, such as the Folstein mini-mental status examination, are rather crude, and it is crucial to develop sensitive and practical neurocognitive function testing to characterize these changes [30]. In particular, the sensitivity of mini-mental status examination has been shown to be problematical in detecting subtle neurocognitive dysfunction in patients with brain metastasis where clinically apparent WBRTinduced dementia is rare (1.9-5.1%) [42,43]. All of these factors can potentially affect the manifestation of changes in neurocognition in a patient with newly developed brain metastases.

Conclusion
Our results show that WBRT with radiosensitizer have not improved the overall survival, local control and tumor response compared to WBRT alone for brain metastases. Despite the use of WBRT with radiosensitizer, outcomes are poor and efforts should be made to incorporate multimodality approaches including surgery and radiosurgery to improve survival. In spite of this apparent negative result, radiosensitizers may be helpful in specific subsets of patients with brain metastases from lung and breast cancers. This can lead to a superior therapeutical ratio by enhancing the benefit derived from whole brain radiotherapy resulting in an improvement of neurocognitive decrease, neurological progression, and quality of life.