NCCN Guidelines Embrace PSMA-PET Imagining for Prostate Cancer

Rarely has a footnote garnered so much positive attention, but a reference in the newly updated prostate cancer guidelines from the National Comprehensive Cancer Network (NCCN) has prostate cancer specialists excited about the prospects for incorporating the highly sensitive imaging modality PSMA-PET into daily practice.

PSMA-PET (prostate-specific membrane antigen positron-emission tomography) involves use of a radiotracer that binds to PSMA and emits positrons that can be detected on PET scans.

The US Food and Drug Administration (FDA) approved the first such imaging agent for use in prostate cancer, Gallium 68 PSMA-11 (Ga 68 PSMA-11), in December 2020.

“Ga 68 PSMA-11 is an important tool that can aid healthcare providers in assessing prostate cancer,” commented Alex Gorovets, MD, from the FDA’s Office of Specialty Medicine in the Center for Drug Evaluation and Research, at that time. “With this first approval of a PSMA-targeted PET imaging drug for men with prostate cancer, providers now have a new imaging approach to detect whether or not the cancer has spread to other parts of the body.”

The footnote in the new NCCN guidelines states that “because of the increased sensitivity and specificity of PSMA-PET tracers for detecting micrometastatic disease compared to conventional imaging (CT, MRI) at both initial staging and biochemical recurrence, the Panel does not feel that conventional imaging is a necessary prerequisite to PSMA-PET and that PSMA-PET/CT or PSMA-PET/MRI can serve as an equally effective, if not more effective, front-line imaging tool for these patients.”

Superior Accuracy

The superior accuracy of this type of imaging was shown in the ProPSMA trial, as previously reported by Medscape Medical News. Imaging with PSMA-PET was shown to have 92% accuracy for the primary outcome of firstline imaging for identifying pelvic nodal or distant metastases, compared with 65% for CT and bone scanning, an absolute difference of 27% (P < .0001). Accuracy was defined as the area under the curve of receiver operating characteristics using a predefined reference standard that included histopathology, imaging, and biochemistry at 6-month follow-up.

Now, with a nod of approval from the NCCN, imaging with PSMA-PET stands ready to gain wider acceptance by clinicians and, equally importantly, by insurers, say experts.

“These molecularly targeted imaging agents are novel, and we’re very excited about their prospects,” said Sophia C. Kamran, MD, a radiation oncologist and assistant professor of radiation oncology at the Massachusetts General Cancer Center, Boston, Massachusetts.

“PSMA-PET has been shown to have more specificity and sensitivity compared to conventional imaging, such as bone scintigraphy and CT scans of the abdomen and pelvis,” she said in an interview.

Jeremie Calais, MD, from the Department of Molecular and Medical Pharmacology at the University of California, Los Angeles, told Medscape Medical News: “it’s more sensitive, it’s more specific, so overall more accurate to detect a localized prostate cancer lesion, so you see more disease with a higher level of confidence when you see something with PSMA-PET than with other imaging techniques.”

Calais said that PSMA-PET is particularly helpful for detecting and staging metastatic lesions in high-risk patients and for detecting and localizing new lesions at recurrence, which may aid in planning focal therapy.

It can also be helpful in restaging recurrent disease before and after second and subsequent lines of treatment, he said.

“The fact that it has now been incorporated into NCCN guidelines is really exciting, because it allows clinicians to use PSMA-PET as a primary imaging modality, when many times it has been shown that, compared to conventional imaging, PSMA-PET will show something where conventional imaging does not show anything,” Kamran said.

Not So Fast

Although there is near universal agreement that PSMA-PET imaging is superior, some prostate cancer specialists say that the new NCCN guidelines may be jumping the gun.

In an opinion piece published in the May 2021 issue of European Urology, Nora Sundahl, MD, PhD, from the University of Ghent, in Ghent, Belgium, and colleagues write: “The recent proPSMA trial assessed the accuracy of PSMA-PET-CT in the diagnostic setting in 302 patients with high-risk prostate cancer as compared to CIM (CT and bone scan). The results suggest better accuracy and frequent management changes with PSMA-PET-CT. On the basis of these results, the authors argue that PSMA-PET-CT staging in this patient group should now become the ‘standard of care’. We would suggest proceeding more cautiously.”

They note that although PSMA-PET is undisputedly more accurate than CT and bone scan, the differences “would probably have been less impressive if surgical staging was used.”

Sundahl and colleagues point to two other trials (OSPREY and a phase 3 trial) that evaluated the diagnostic accuracy of PSMA-PET. Both showed a sensitivity of about 40%, compared with the 85% reported in the proPSMA trial.

“Importantly, even if the reported accuracy rate in the proPSMA trial is true, the fundamental question whether improved staging can improve clinical outcomes in prostate cancer patients remains unanswered,” the editorialists comment.

They also caution about the risk of upstaging and overtreatment, citing as an example a patient with disease that is deemed to be nonmetastatic on bone scan and CT but is ruled as metastatic by PET-PSMA, owing to PSMA’s avidity for malignant cells.

“In the proPSMA trial, more than a quarter of the patients randomized to CIM crossed over to PSMA-PET-CT and had a treatment management change based on the second-line imaging, including 14 patients changing from a curative-intent to a palliative-intent treatment,” Sundahl and colleagues write. “Is it correct to assume that this treatment switch necessarily leads to better patient outcomes? Furthermore, are we sure that the distant lesions on PSMA-PET-CT were evidence of metastases?”

The editorialists call for additional evidence to support PSMA-PET before allowing the technology to “usurp” current staging methods and clinical management of patients with prostate cancer. They suggest that a randomized clinical trial be conducted comparing CIM and treatment with PSMA-PET in which crossover to the experimental technique is not allowed.

Calais pointed out that for all NCCN recommendations, quality of evidence is of level 2a or higher, meaning that at a minimum, the recommendation must be supported by systematic reviews with homogeneity of either retrospective cohort studies or untreated control participants in randomized trials.

The NCCN guideline recommendations were based on the proPSMA results and other nonrandomized studies. The guideline authors acknowledge that PSMA-PET may not make a difference in clinical outcomes.

“The Panel notes that false-positive rates are high with nuclear imaging; therefore, histologic confirmation is strongly recommended whenever feasible. Moreover, these PET/CT and PET/MRI tests are expensive, and, whereas results may change treatment, they may not change oncologic outcome,” the NCCN authors acknowledge.

Kamran and Calais have disclosed no relevant financial relationships.

Eur Urol. 2021 May;79:565-567. Abstract

Neil Osterweil, an award-winning medical journalist, is a long-standing and frequent contributor to Medscape.

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