Clear cell renal cell carcinoma (RCC) comprises 80% of all primary kidney malignancies and causes 90% of kidney cancer deaths. But it is notoriously tough to diagnose.
RCC is not easily distinguished from other types of renal masses using standard radiologic tools such as CT, MRI, and ultrasound. Blood tests, including those that measure cell-free or circulating tumor DNA, can’t rule it out. Even a definitive histologic diagnosis is not always possible prior to treatment, which is why most patients with suspected tumors are treated surgically without first undergoing biopsy.
Renal masses are usually discovered incidentally during imaging, before patients have any symptoms, and increased use of imaging in healthcare has led to more of these lesions being found. This, in turn, has led to many patients receiving aggressive treatment for small tumors that are either benign — as nearly one third turn out to be — or too slow-growing to pose a threat.
In older patients with comorbidities, who represent a large share of RCC cases, surgical treatment can be associated with poor outcomes and prolonged recovery.
“Patients who are elderly, whose cancers are indolent, are going in for treatment when their tumors probably could be safely observed — but they’re anxious because they don’t know the natural history of the tumor,” said Brian Shuch, MD, a urologic oncologist at the University of California, Los Angeles.
To help people make more appropriate treatment decisions, “we need to be able to quickly identify something as cancer, and whether it is a cancer that is more likely to grow and spread if not treated at a smaller size.”
PET imaging using immunoPET tracers is a noninvasive imaging technique that has “revolutionized the management of prostate cancer and neuroendocrine cancers,” Shuch said. Urologists have long hoped for a PET molecular imaging agent that can reliably diagnose kidney cancer, reducing unnecessary biopsies and surgeries, he continued.
Investigators Compare Renal Mass Scan Results With Histologic Findings
In October, Shuch and his colleagues published results from a randomized, open-label trial of [89Zr]Zr-girentuximab, an experimental radiolabeled antibody that detects carbonic anhydrase 9 (CAIX), a cell surface marker overexpressed in clear cell RCC.
The investigators compared their scan results with histologic findings from 300 patients operated on for an uncharacterized renal mass < 7 cm. They reported that [89Zr]Zr-girentuximab PET-CT was 85.5% sensitive (95% CI, 81.5-89.6) and 87% specific (95% CI, 81.0-93.1) in detecting clear cell RCC.
The technology picked up small lesions as easily as large ones, the investigators found. Its positive predictive value was 93%, and all 11 false-positive lesions indicated some type of malignancy other than clear cell RCC. These included papillary carcinomas and other renal cancer types, making the scans strongly positively predictive of renal cancer in general.
The findings could change the standard of care for kidney cancer diagnostics, Shuch said. If the technology is approved by the US Food and Drug Administration, “I think it will reduce the need for biopsy — the centers that are doing biopsy often will turn to this first.”
Much of the urology community is already used to ordering nuclear tracers for prostate cancer, he noted, so extending the approach to kidney cancer would not be difficult.
It is not just older, frailer patients who stand to benefit from the scans. Recently, during a post-trial registry study at his institution, Shuch and his colleagues performed one on a woman in her 30s with a small renal mass.
“Young women can have a benign tumor called a fat-poor angiomyolipoma,” he said. “We did the scan and it was negative, removing the likelihood that she had clear cell RCC. She ultimately was biopsied, and it confirmed our suspicion that she had a fat-poor angiomyolipoma. Now she knows that she will likely never need treatment unless it grows to a very large size. And even then, she wouldn’t need a surgery; she can have a transarterial embolization of the tumor by an interventional radiologist.”
Scans Are Easy to Read
Jeremie Calais, MD, PhD, a nuclear medicine specialist at UCLA who works closely with Shuch’s group, said that the [89Zr]Zr-girentuximab scans “are easy to read,” readily distinguishing clear cell RCC from background kidney tissue.
Calais thinks the technology will also prove useful in kidney cancer staging. “This scan targets CAIX in the whole body. So it would show on a whole-body level where CAIX is highly expressed. And once you locate it, you can look at the cross-sectional images to get a better understanding of the source of this expression, which is usually a lesion,” he said.
Shuch noted that the current trial was designed only to see how well the scans picked up primary tumors. He is leading a separate study that seeks to determine whether the scans perform better than conventional imaging in patients treated for clear cell RCC who have a high risk for recurrence.
“The future will be to see if this can detect lesions outside the kidney, in lymph nodes, in lung, in brain and bone. This would be a big game changer to how we evaluate for distant spread,” Shuch said.
Both investigators said that the new findings open the door for so-called theranostic approaches, which use radiopharmaceuticals binding to the same molecular target visualized by PET imaging to bring radiation treatment to the cells expressing that target.
“It’s therapy and diagnostics using the same molecular targets,” Calais explained. “So with the diagnostic, you’re looking to see whether the target is expressed. And the radiotherapeutic agent goes to the same target” — in this case, CAIX and the cancer cells expressing it. Of note, CAIX is overexpressed by clear cell RCC, but also possibly by other cancers when they have low levels of oxygen.
For clear cell RCC, the same antibody — girentuximab — would be used in both diagnosis and treatment, but the radioisotopes would be different. “Instead of one that emits low-dose radiations that go out of the body and that you can detect with scanners, you’d use one that is very short range and delivers high radiation where the target is expressed,” killing cancer cells, Calais said,
Shuch and colleagues’ study was funded by Telix Pharmaceuticals, the manufacturer of the investigational technology. Shuch disclosed financial relationships with Telix, Veracyte, Merck, Johnson & Johnson, and others. Calais disclosed financial relationships with Telix, Novartis, Curium, Lantheus, and others.