Abstract
BackgroundRe-excision due to positive margins following breast-conserving surgery (BCS) negatively affects patient outcomes and healthcare costs. The inability to visualize margin involvement is a significant challenge in BCS. 5-Aminolevulinic acid hydrochloride (5-ALA HCl), a non-fluorescent oral prodrug, causes intracellular accumulation of fluorescent porphyrins in cancer cells. This single-center Phase II randomized controlled trial evaluated the safety, feasibility, and diagnostic accuracy of a prototype handheld fluorescence imaging device plus 5-ALA for intraoperative visualization of invasive breast carcinomas during BCS.MethodsFifty-four patients were enrolled and randomized to receive no 5-ALA or oral 5-ALA HCl (15 or 30 mg/kg). Forty-five patients (n = 15/group) were included in the analysis. Fluorescence imaging of the excised surgical specimen was performed, and biopsies were collected from within and outside the clinically demarcated tumor border of the gross specimen for blinded histopathology.ResultsIn the absence of 5-ALA, tissue autofluorescence imaging lacked tumor-specific fluorescent contrast. Both 5-ALA doses caused bright red tumor fluorescence, with improved visualization of tumor contrasted against normal tissue autofluorescence. In the 15 mg/kg 5-ALA group, the positive predictive value (PPV) for detecting breast cancer inside and outside the grossly demarcated tumor border was 100.0% and 55.6%, respectively. In the 30 mg/kg 5-ALA group, the PPV was 100.0% and 50.0% inside and outside the demarcated tumor border, respectively. No adverse events were observed, and clinical feasibility of this imaging device-5-ALA combination approach was confirmed.ConclusionsThis is the first known clinical report of visualization of 5-ALA-induced fluorescence in invasive breast carcinoma using a real-time handheld intraoperative fluorescence imaging device.Trial registrationClinicaltrials.gov identifier NCT01837225. Registered 23 April 2013.
Highlights
Breast cancer, the most prevalent cancer in women, is often treated by breast-conserving surgery (BCS) [1, 2] which aims to completely excise the tumor with clear margins while preserving the maximum amount of healthy tissue
We present the results of a single-center non-interventional Phase II randomized controlled trial (RCT) designed to characterize the imaging performance of our handheld imaging device with two doses (15 and 30 mg/kg BW) of 5-aminolevulinic acid (5-ALA) HCl versus no tumor contrast in patients with invasive breast cancer undergoing lumpectomy or mastectomy
Subject demographics Forty-five females (29–83 years old) undergoing lumpectomy (n = 29) or mastectomy (n = 16) for primary ductal (n = 37), lobular (n = 7), or mixed (n = 1) invasive carcinoma at the Princess Margaret Cancer Center (PMCC, Toronto, Ontario, Canada) between August 2013–August 2018 were included in the analysis (Table 1)
Summary
The most prevalent cancer in women, is often treated by breast-conserving surgery (BCS) [1, 2] which aims to completely excise the tumor with clear margins while preserving the maximum amount of healthy tissue. BCS best practice uses WL visualization, palpation, specimen radiography, and intraoperative histopathology to guide resection. These techniques are lengthy (~ 20 min) [23], limited by inaccurate colocalization of positive margins on the excised tissue to the surgical bed [24] and variably impact outcomes [23]. Re-excision due to positive margins following breast-conserving surgery (BCS) negatively affects patient outcomes and healthcare costs. 5-Aminolevulinic acid hydrochloride (5-ALA HCl), a non-fluorescent oral prodrug, causes intracellular accumulation of fluorescent porphyrins in cancer cells This single-center Phase II randomized controlled trial evaluated the safety, feasibility, and diagnostic accuracy of a prototype handheld fluorescence imaging device plus 5-ALA for intraoperative visualization of invasive breast carcinomas during BCS
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