ON JUNE 6, the U.S. Food and Drug Administration (FDA) approved aminolevulinic acid hydrochloride, known as ALA HCl (Gleolan), as an optical imaging agent indicated in patients with gliomas (suspected World Health Organization [WHO] grades III or IV) for preoperative imaging, as an adjunct for the visualization of malignant tissue during surgery.
The efficacy of 20 mg/kg of ALA was evaluated in three clinical trials involving patients 18 to 75 years old who had a preoperative magnetic resonance image (MRI) compatible with high-grade (WHO grade III or IV) glioma and were undergoing surgical resection.
Studies Leading to Approval
STUDY 1 INCLUDED 33 patients with newly diagnosed glioma and study 2 included 36 patients with recurrent glioma. Both open-label studies compared fluorescence to tumor status, using histopathology as the reference standard.
Study 3 was a randomized, multicenter study in 415 patients with a preoperative diagnosis of high-grade glioma by MRI. Patients were randomized to ALA fluorescence arm or to white light control arm. In 349 patients, high-grade glioma was confirmed by a blinded central read and histopathology. In patients with confirmed high-grade glioma randomized to the ALA fluorescence arm, the presence of fluorescence at a biopsy level was compared to tumor status using histopathology as the reference standard.
A total of 297, 370, and 479 biopsies were obtained in studies 1, 2 and 3, respectively. True-positive biopsies (ie, biopsies that were positive by histopathology and fluorescence) were 178, 342, and 312, respectively. False-positive biopsies (ie, biopsies that were negative by histopathology and positive by fluorescence) were 7, 12, and 7, respectively. True-negative biopsies were 27, 3, and 30, respectively. False-negative biopsies were 85, 13, and 130, respectively.
The extent of resection among study 3 patients with confirmed high-grade glioma in the ALA fluorescence arm was compared to that among patients in the control arm, with the “completeness” of resection being determined by a central blinded read of early postsurgical MRI. Percentage of patients who had “completeness” of resection was 64% in the ALA arm and 38% in the control arm, with the difference of 26% (95% confidence interval [CI] = 16%–36%).
The safety of ALA is supported by 5 clinical trials that included 527 patients with glioma.
Safety and Adverse Reactions
ALA IS ASSOCIATED WITH such risks as phototoxic reactions, hypersensitivity reactions, and interpretation errors (false-negatives and false-positives). An increase in the extent of resection might increase the risk of serious neurologic deficits in the short term.
Adverse reactions that occurred in > 1% of patients in the week following surgery were pyrexia, hypotension, nausea, and vomiting. Adverse reactions occurring in < 1% of patients in the first 6 weeks after surgery were chills, photosensitivity reaction, solar dermatitis, hypotension, abnormal liver function test, and diarrhea. One patient experienced respiratory failure due to drug overdose. ■
