NCCN Guidelines - Staging Evaluation and Imaging Approaches in Prostate Cancer – Christopher Wallis and Zachary Klaassen

November 7, 2021

Christopher Wallis and Zachary Klaassen, continue their discussion on the NCCN clinical practice guidelines in oncology focusing on prostate cancer and the recently released and published update of these guidelines from September 2021. In this conversation the pair focus on questions relating to the initial clinical assessments, staging evaluation, and imaging approaches in prostate cancer.

Biographies:

Christopher J.D. Wallis, MD, Ph.D., Assistant Professor in the Division of Urology at the University of Toronto.

Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Georgia Cancer Center


Read the Full Video Transcript

Christopher Wallis: Hello and thank you for joining us for this UroToday sponsored discussion of the NCCN clinical practice guidelines in oncology with a focus on the prostate cancer guidelines.

This is a recently released and published update of these guidelines from September 2021. Today, we are focusing on questions relating to the staging evaluation and imaging approaches in prostate cancer. I'm Chris Wallis, an Assistant Professor in the Division of Urology. With me is Zach Klaassen, an Assistant Professor in the Division of Urology at the Medical College of Georgia.

As you can see here, we're going to focus on two large questions, the idea of initial clinical assessments, and staging evaluation, and then imaging techniques.

In terms of the initial clinical assessment and staging, we need to consider when best to deploy these studies and so staging and its utility depends on both the patient and disease characteristics. For patients with very low, low, or intermediate prostate cancer who have a short life expectancy and are asymptomatic, imaging is not required and staging does not contribute meaningfully to the care of these patients. In contrast, when we move on to patients who have high or very high-risk disease, who still have a relatively short life expectancy, there is evidence of benefit for bony imaging across the board, whereas pelvic and abdominal imaging should be provisioned based on the predicted risk of nodal involvement from nomograms.

In symptomatic patients, bony imaging is always warranted, then advanced imaging can be applied to adjudicate equivocal findings but the majority of our patients who have a life expectancy greater than five years, those with unfavorable intermediate, high, or very high-risk disease typically benefit from bony imaging along with pelvic plus or minus abdominal imaging.

We are now going to transition into questions of how we can assess pelvic or abdominal imaging for nodal disease. And this is recommended for those with intermediate or high-risk disease when a nomogram indicates a greater than 10% chance of nodal involvement. However, the NCCN guideline panel notes that this imaging approach may only actually be cost-effective when the nomogram-derived risk is greater than 45% for nodal involvement, though the recommendation remains for its use much earlier. As we can expect and contribute to the disease categorizations, PSA, Gleason score, and clinical T stage are each independently associated with the likelihood of nodal involvement. And validations of these studies have shown that the use of a 10% threshold by nomogram has a very high negative predictive value of 99.5%. The panel also notes that multiparametric MRI is preferred over CT scan for assessment of nodal involvement, which varies from historical practice patterns, using a CT abdomen and pelvis.

We now can consider specific imaging approaches and so we are going to start off with an overview and the rationale for imaging in prostate cancer as in most cancers is to detect and characterize the disease burden in order to appropriately select treatment or guide changes in management. And the approaches we can take are divided broadly into anatomic or functional imaging. And for the most part, we relied on anatomic imaging for the characterization of disease with CT and MRI forming the basis of our staging and ultrasound, helping us to guide local prostate biopsies and functional imaging with technetium-based bone scans that have been the standard practice for many decades. Although more recently, we are evolving beyond this to include PET/CT, and PET/MRI, as well as multiparametric MRI, which includes functional sequences. The utility of imaging in prostate cancer patients depends on both patient and tumor characteristics and we will talk through some of these.

First, we're going to discuss multiparametric MRI in prostate cancer. Over the last decade or so we've seen rapidly increasing utilization. And when we talk about multiparametric MRI, what we mean is anatomic T2 weighted sequences, as well as at least one additional sequence. This additional sequence typically includes diffusion-weighted imaging and may also include dynamic contrast-enhanced imaging. Typically if only two sequences are used, the expression biparametric MRI is employed and this is often done to spare the use of contrast. The NCCN guideline panel stated that a high-quality MRI requires the use of a three Tesla magnet while the need for an endorectal coil remains controversial, although some regions in the world and some groups are using a 1.5 Tesla magnet still.

MRI has demonstrated benefit across the whole spectrum of prostate cancer and I've highlighted a few examples here beginning with an initial diagnosis where a pre-biopsy MRI can help guide fusion biopsies, which increase the diagnosis of high-grade clinically significant tumors and decrease the diagnosis of clinically insignificant disease. MRI may also help inform the selection of patients for active surveillance as we know that MRI visible Gleason six disease has a higher risk of progression. MRI may be useful in local staging and has a very high negative predictive value for extracapsular extension in men who are otherwise low risk. As we alluded to before, an MRI may contribute to nodal staging as is equivalent to CT for the detection of pelvic lymphadenopathy. And finally, MRI actually outperformed both bone scan and x-ray for bony staging with sensitivities of 98% to 100% and specificity similarly high.

Now we are going to transition over to a discussion of nuclear imaging, and at this point in time, I will pass it over to Zach to walk us through this part of the updated guideline.

Zachary Klaassen: Thanks, Chris. When we look at nuclear imaging in prostate cancer, the use of PET/CT or PET/MRI for the staging of low volume recurrent or metastatic disease is rapidly developing. And certainly, there is variability in equipment and protocols, interpretation at institutions, and providing challenges for application interpretation. Importantly, given the FDA clearance, clinical trials are unlikely to assess utility on oncology outcomes.

As you can see here, there are three different types of nuclear imaging, choline PET/CT, the fluciclovine or Axumin PET/CT, and sodium fluoride PET/CT. These sensitivities and specificities are in the biochemical recurrent setting with similarities between these three imaging modalities. However, previous studies in biochemical recurrence settings have found that choline PET and fluciclovine PET show an 85% agreement, and in men with biochemical recurrence after local therapy, sodium fluoride PET detected bone metastases not seen on CT or bone scan in 16.2% of patients. Ultimately, the panel believes that these may be used in biochemical recurrence for further soft tissue or bone evaluation after bone scans, chest CT and abdominal CT or MRI.

However, there are several cautionary statements that the NCCN panel does provide. The panel believes that sodium fluoride, choline PET, and fluciclovine PET/CT or PET/MRI may be considered after a bone scan when the results are equivocal. Secondly, the panel cautions however that early detection of bone metastatic disease may result in earlier use of newer and more expensive therapies, which may or may not improve oncological outcome or overall survival.

As Chris mentioned, this is an updated version of the NCCN guidelines and new updates as of September 2021 are provided in this updated setting. First, there are multiple PSMA radiopharmaceuticals at various stages of investigation and the NCCN guidelines now recommend a DCFPyL and gallium-PSMA-11. A PSMA PET/CT can be considered as an alternative to standard imaging for staging, detection of biochemical recurrence, and workup for progression as conventional imaging is not a prerequisite for their use.

Looking further at DCFPyL and gallium-PSMA PET compared to fluciclovine or choline PET, there are higher detection rates due to higher sensitivity, particularly at lower levels, which is important in the biochemical recurrent setting. And secondly, compared to conventional imaging and staging of high-risk patients, both DCFPyL and gallium-PSMA PET are more accurate in this setting.

In terms of summarizing the nuclear imaging section, false-positive rates may be high therefore histological confirmation is recommended whenever feasible. However, the risk of false positives is outweighed by the increase in true positives in this setting. The guideline panel emphasizes the potential for the Will Rogers phenomenon in the setting of increasing utilization of advanced imaging, whereby PET imaging may be expensive and while they can change treatment, they may not change downstream oncological outcomes.

Next, we are going to transition to the risks of imaging.

Certainly, risks of imaging include concrete and tangible risks, as well as other risks that are less clear. This includes the risk of ionizing radiation, adverse reactions to contrast, false positives, and overdetection.

Ionizing radiation is associated with x-ray, CTs, and PET/CT scans. And we can see here that there are deterministic risks that occur at a certain level and without effects below that certain level, and this includes cataracts or radiation burns, which is rarely relevant for discussing medical imaging. However, what is relevant for medical imaging is stochastic effects or later effects, which increase with dose with no safe threshold. And the major concern in this setting is radiation-induced malignancies. There is no direct radiation measurement so this is inferred from other models. This is a small but finite, though poorly quantified risk that is higher in younger patients, such as those that are getting imaging for testicular cancer follow-up.

Contrast reactions are also something we discuss on a daily basis. Many imaging approaches rely on contrast media, whether this is oral, IV, or rectal. Iodinated intravenous contrast reactions typically are just mild skin reactions but they can occasionally lead to severe life-threatening conditions. The risk is quite low with non-ionic contrast and renal function may be affected by both CT and MRI contrast medium.

There are several lymph limitations of imaging approaches that are notable in terms of technical limitations, with regards to sensitivity, specificity, and accuracy. And these are further modulated by the expertise of the interpreting physician. As we know, harm may arise from false negatives in the terms of failure to identify the tumor or tumor recurrence or false positives leading to the burden of overtreatment and subsequent cost.

In summary, in this section, imaging is a critical tool in the evaluation of managing patients with prostate cancer. However, it is not without risk and should be used judiciously, particularly with patients and system-derived harms from inappropriate use of imaging. Algorithmic use of imaging, such as the ACR criteria can assess the medical decision making, and ultimately challenging imaging cases are best addressed through direct communication between ordering and interpreting physicians either directly or through a multidisciplinary approach.

Thank you very much, and we hope you enjoyed this NCCN discussion of the prostate cancer guidelines and imaging specifically.
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