NEW YORK – New data from a study on the use of mass spectrometry in kidney cancer surgery could lay a path for clinical development of the tool as a means to improve the success of surgical procedures and patient outcomes.
The concept — that mass spec can distinguish the presence or absence of residual tumor tissue by measuring cancer-associated metabolites — has been explored in different contexts over the last several years. Notably, investigators from the University of Texas were able to develop a hand-held device allowing investigation of margins in real time in the operating room without the need to send samples to a lab.
Thus far, these techniques haven't broken into the clinic. But with the new kidney cancer study, published in JCO Precision Oncology last month, investigators are hopeful that they are on the road to clinically validating their approach and bringing it into practice.
Stanford Urologist James Brooks, senior author of the new report, said that he and others, including the developers of the hand-held "MassSpec Pen" device, have studied mass spec as a surgical margin tool across tumor types, including in pancreatic, breast, stomach, kidney, and prostate cancer, largely using a ubiquitous technique called desorption electrospray ionization mass spectrometric imaging (DESI-MSI).
The team employed the same methodology in this latest study. Building upon an earlier proof of concept that was limited to clear cell renal carcinoma (ccRC), investigators expanded their classifier to detect and distinguish normal kidney tissue from papillary RCC (pRCC), chromophobe RCC (chRCC) and ccRC.
"One big struggle we have [in kidney cancer] is determining whether or not we've cut across the cancer, which is what we call positive surgical margins. This technology intrigued me and some of my colleagues because it offers a [speedy] alternative to intraoperative frozen sections," which, despite being the current standard, are often eschewed in kidney tumor surgery because of their long turnaround time, Brooks said.
"The operation that we do fairly commonly is called partial nephrectomy, where you clamp off the blood vessels to the kidney and take the tumor out, and you [want to see] normal tissue around it to get negative margins," he explained. If there is a suspicion that not everything was removed, a surgeon will send tissue for frozen section analysis.
The issue for these surgeries is that the kidneys get what Brooks said is about 25 percent of the body's cardiac output. "It's a very bloody organ, so you clamp off the vessels and you work as fast as you can to get the tumor out."
"If you've sent out for a frozen section, it can take 30 to 60 minutes to get the results back, and you just can't sit with the kidney clamped that whole time. You'll kill the kidney. So, what people do is they close up that hole that they have left from removing a tumor." If the results come back with positive margins, the patient has to be subjected to another difficult and bloody resection.
In the study, Brooks and his colleagues trained a multinomial lasso classifier to distinguish all histological subtypes of renal cell carcinoma from normal kidney tissues using a computational pipeline for raw DESI-MSI data called MassExplorer.
Among an initial training set of 64 tissues, the team's classifier demonstrated 87 percent sensitivity and almost 83 percent specificity. When tested in an independent sample set including 48 samples from Stanford and another 57 from UT Austin, the classifier showed 87 percent sensitivity and 79 percent specificity.
Authors wrote that this represents excellent performance "matching or exceeding those reported for frozen sections and providing strong rationale for developing a rapid and reproducible DESI-MSI–based method of assessing cancer margins during surgical resection of RCC to potentially lower the risk of tumor recurrence."
The next step for the team will be to perform larger analytical validation studies and then potentially a prospective clinical study in which mass spec is performed in parallel with frozen sections so that results and patient outcomes can be directly compared.
According to Brooks, the existence of "enabling technologies," like the Texas team's MassSpec Pen offer even more encouragement that clinical translation is on the way. Livia Eberlin, the pen's inventor, is also a co-author on the JCO Precision Oncology study.
"It's a sterilizable probe that the surgeon can actually hold in [their] hand and scan over tissue and get mass spec readings, so you don't even have to cut a frozen section," Brooks said. "You can use it with laparoscopic cases. You can use it with open cases."
According to Brooks, this added value means the most likely path in kidney cancer and other tumor types will be to continue with studies employing the pen in retrospective samples and then use that data to move forward to a prospective trial.
He cited a growing body of preliminary prospective data, including pancreas, breast, and brain tumor studies, in which the majority of cases with a positive mass spec result and negative frozen section turned out to have cancer in their margin samples when non-frozen, standard pathology was performed.
In studies of pancreatectomy samples, researchers have found more than 98 percent agreement between DESI-MSI and pathology, the Stanford authors wrote.
Similar data has also hinted at long-term outcomes, Brooks said, with researchers observing that pancreatectomy patients with clear margins by DESI-MSI had significantly better outcomes than patients with positive mass spec results but negative margins by frozen section.
Brooks said that despite these promising findings, it's far too early to tell for sure if this benefit will bear out in clinical validation. "The cases have been on the order of a few hundred at this point or less than that in some cases. That being said, the signal's pretty doggone strong, and with a strong signal you can probably show some benefit with a relatively modest-size clinical trial."
If the right trials can be completed, Brooks estimated that tools like the MassSpec Pen could be entering the operating room in five to 10 years. "All this entails money of course … but I'm enthusiastic about the potential," he added.