Increasing nerve-sparing radical prostatectomy rates using intraoperative nonlinear microscopy

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Prostate cancer is the most common cancer in the US male population, with an estimated 160,000 new cases in 2018. Treatment with radical prostatectomy (RP), complete surgical excision of the prostate, results in favorable oncologic outcomes with long-term survival benefits. Nerve-sparing RP is favored if cancer does not involve the neurovascular bundles since patients have better recovery of sexual function and continence, major factors determining postoperative quality of life. However current preoperative methods do not accurately identify patients who could be treated by nerve-sparing RP. The NeuroSAFE study, Schlomm, et al., 2012 demonstrated that comprehensive intraoperative frozen section analysis (FSA) of margins near the neurovascular bundles increased the rate of nerve-sparing RPs. However comprehensive intraoperative FSA required extensive time and personnel, which is impractical for most hospitals. Nonlinear microscopy (NLM) can generate images of freshly excised tissue resembling H&E histology, without freezing or microtoming, reducing the time and labor required for pathology evaluation. We developed custom NLM technology and specimen handing/staining protocols for rapid, high-throughput evaluation of prostatectomy specimens. Our preliminary data demonstrates that NLM detects prostate cancer with 97% sensitivity and 100% specificity compared to formalin fixed paraffin embedded (FFPE) H&E in a study of 122 RP specimens from 40 patients with blinded reading by three pathologists. NLM promises to enable intraoperative evaluation of RP specimens with a simplified workflow that is practical for widespread clinical adoption. Our hypothesis is: NLM can be used to rapidly assess prostate surgical specimens and increase nerve-sparing RP rates without increasing positive margin rates. This is a collaborative, multidisciplinary program with investigators at the Massachusetts Institute of Technology and Beth Israel Deaconess Medical Center (BIDMC), Harvard Medical School. Aim 1 will develop next generation NLM technology and clinical workflow for rapid, comprehensive evaluation of prostate specimens in RP. These advances will enable a two person team (histotech/resident and pathologist) to perform comprehensive NLM of RP margins adjacent to the neurovascular bundles, faster and with much fewer personnel than NeuroSAFE. Aim 2 will perform a randomized controlled trial with patients undergoing robotic RP. The primary endpoints will be the rate of nerve-sparing RPs and rate of positive surgical margins in areas adjacent to the neurovascular bundles in a study group receiving intraoperative NLM margin assessment and standard-of-care postoperative FFPE histology versus a control group receiving standard-of-care FFPE postoperative histology. The secondary endpoints will be agreement between intraoperative NLM versus postoperative histology in the study arm and surgical times in the study arm versus control arm. Aim 3 will develop NLM technology and workflows that enable remote NLM evaluation which would increase access to pathologists with subspecialty expertise, streamline pathologist workflow, and facilitate adoption of intraoperative margin assessment in RP.