Elsevier

The Lancet Oncology

Volume 7, Issue 5, May 2006, Pages 392-401
The Lancet Oncology

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Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial

https://doi.org/10.1016/S1470-2045(06)70665-9Get rights and content

Summary

Background

5-aminolevulinic acid is a non-fluorescent prodrug that leads to intracellular accumulation of fluorescent porphyrins in malignant gliomas—a finding that is under investigation for intraoperative identification and resection of these tumours. We aimed to assess the effect of fluorescence-guided resection with 5-aminolevulinic acid on surgical radicality, progression-free survival, overall survival, and morbidity.

Methods

322 patients aged 23–73 years with suspected malignant glioma amenable to complete resection of contrast-enhancing tumour were randomly assigned to 20 mg/kg bodyweight 5-aminolevulinic acid for fluorescence-guided resection (n=161) or to conventional microsurgery with white light (n=161). The primary endpoints were the number of patients without contrast-enhancing tumour on early MRI (ie, that obtained within 72 h after surgery) and 6-month progression-free survival as assessed by MRI. Secondary endpoints were volume of residual tumour on postoperative MRI, overall survival, neurological deficit, and toxic effects. We report the results of an interim analysis with 270 patients in the full-analysis population (139 assigned 5-aminolevulinic acid, 131 assigned white light), which excluded patients with ineligible histological and radiological findings as assessed by central reviewers who were masked as to treatment allocation; the interim analysis resulted in termination of the study as defined by the protocol. Primary and secondary endpoints were analysed by intention to treat in the full-analysis population. The study is registered at http://www.clinicaltrials.gov as NCT00241670.

Findings

Median follow-up was 35·4 months (95% CI 1·0–56·7). Contrast-enhancing tumour was resected completely in 90 (65%) of 139 patients assigned 5-aminolevulinic acid compared with 47 (36%) of 131 assigned white light (difference between groups 29% [95% CI 17–40], p<0·0001). Patients allocated 5-aminolevulinic acid had higher 6-month progression free survival than did those allocated white light (41·0% [32·8–49·2] vs 21·1% [14·0–28·2]; difference between groups 19·9% [9·1–30·7], p=0·0003, Z test). Groups did not differ in the frequency of severe adverse events or adverse events in any organ system class reported within 7 days after surgery.

Interpretation

Tumour fluorescence derived from 5-aminolevulinic acid enables more complete resections of contrast-enhancing tumour, leading to improved progression-free survival in patients with malignant glioma.

Introduction

Malignant gliomas are locally invasive tumours that have poor prognosis despite treatment with a combination of surgery, radiotherapy, and chemotherapy. A trial by the European Organisation for Research and Treatment of Cancer (EORTC)1 showed that overall survival was 2 months higher with concomitant adjuvant radiochemotherapy with temozolomide followed by adjuvant temozolomide than with radiotherapy alone. Further analyses2 showed that patients who had previously had complete resection derived the most benefit from the temozolomide regimen compared with those who had had incomplete resection (4·1 months vs 1·8 months overall survival). Thus, in addition to the survival benefit associated with maximum cytoreductive surgery,3, 4, 5, 6, 7 such surgery seems essential for the efficacy of modern adjuvant treatment. However, past surgical studies4, 5, 6, 7, 8, 9 have noted that complete resection of contrast-enhancing tumour is achieved in fewer than 20% of patients, suggesting difficulty in defining marginal, enhancing tumour intraoperatively.4

5-aminolevulinic acid is a natural biochemical precursor of haemoglobin that elicits synthesis and accumulation of fluorescent porphyrins in various epithelia and cancerous tissue;10 it also results in accumulation of porphyrins within malignant glioma tissue. Porphyrin fluorescence can be visualised by use of a modified neurosurgical microscope, and has been investigated for identification of residual malignant glioma intra-operatively, with the aim of improving surgery.11, 12 Because of its intratumoral synthesis, 5-aminolevulinic acid differs from other fluorescing agents that have been investigated for tumour discrimination such as fluorescein,13 which penetrates malignant gliomas via the defective blood-brain barrier.

We aimed to do a randomised controlled trial to assess the use of porphyrin fluorescence in malignant glioma after administration of 5-aminolevulinic acid for improving resection as defined by postoperative MRI, and to analyse the effect of resection on progression-free survival, neurological morbidity, and type and frequency of treatment after progression.

To allow premature termination of the study, a confirmatory interim analysis was scheduled after 270 of 350 planned patients had been recruited in the full-analysis population. This report gives the results of the interim analysis, which resulted in termination of the study as defined in the protocol.

Section snippets

Patients

Individuals aged 18–72 years with suspected (as assessed by study surgeon), newly diagnosed, untreated malignant glioma and who were eligible for surgery acording to the study surgeon were eligible for trial participation. The protocol stipulated that patients had tumours with a distinct ring-like pattern of contrast-enhancement with thick irregular walls on MRI, and a core area of reduced signal suggestive of tumour necrosis as assessed at the study centre by the study surgeon.

Exclusion

Results

From Oct 11, 1999, 322 patients were enrolled by 32 investigators at 17 German study centres. The last visit for the interim analysis was done on July 19, 2004. 161 patients were randomly assigned to fluorescence-guided surgery with 5-aminolevulinic acid, and 161 were randomly assigned to conventional microsurgery with white light. Figure 1 shows the trial profile.

At central review, 34 patients did not meet histological criteria and were thus excluded from the full-analysis and per-protocol

Discussion

We have shown that use of 5-aminolevulinic acid leads to a higher frequency of complete resections of contrast-enhancing tumour on early postoperative MRI, translating into higher progression-free survival, than does conventional microsurgery guided by white light. Postoperative Karnofsky performance score, neurological status, and toxic effects were much the same for both groups, showing fluorescence-guided surgery with 5-aminolevulinic acid to be safe. Overall survival did not differ between

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