Volume 17, Issue 1
The PET Center of Excellence Newsletter is a quarterly member information service published under the direction of the PET CoE leadership and SNMMI
IN THIS ISSUE
PET Center of Excellence
1Capital Health Advanced Imaging, Trenton, NJ. 2Department of Radiology, University of Pennsylvania, Philadelphia, PA. 3University of Pennsylvania Health System, Philadelphia, PA.
|Please Note: This article is available for CE/SAM credit at http://ow.ly/pWRJ30rB4RB,
free to PET CoE members.
Cancer biomarkers measure specific biological properties of disease for characterization, prognosis, or prediction (1). Advances in tissue and blood biomarker research have transformed the treatment of many malignancies, with several biomarkers now incorporated into routine clinical practice (2). Complementary to laboratory-based techniques, noninvasive molecular imaging biomarkers with distinct advantages and considerable promise have emerged (3). This article reviews biomarkers in oncology, with a focus on imaging biomarkers. The incorporation of imaging biomarkers into clinical trials in an integrated or integral role is discussed, with representative examples of each category highlighted. Potential future directions for molecular imaging in clinical trials are explored.
A biological marker, or biomarker, is a measure of a biological attribute that can be used to characterize a normal or pathologic process or to measure a pharmacologic response to an intervention. In characterizing disease, biomarkers have been utilized for diagnosis, staging, prognosis, and prediction of response (4). Two examples of tissue-based biomarkers with established roles in clinical medicine are discussed below, underscoring the role of biomarkers in selecting patients for appropriate treatment.
In breast cancer, a commercial 21-gene recurrence score assay, Oncotype DX (Genomic Health), has been utilized to direct therapy in hormone-receptor–positive cancers. A low score on this tissue-based assay predicts a low risk of recurrence without chemotherapy, whereas a high score predicts benefit from chemotherapy. The TAILORx clinical trial studied patients with mid-range recurrence scores, as the possible benefit of chemoendocrine therapy over endocrine therapy was not known (5). Patients with mid-range scores were randomly assigned to 2 treatment groups (6,711 patients in total). Endocrine therapy was shown to be similar to chemoendocrine therapy, with only a small benefit seen in a subset of patients aged 50 years or younger with a certain range of recurrence scores. This trial adds to the body of knowledge supporting the use of this tissue-based test in selecting patients for appropriate therapy and sparing patients from unnecessary, toxic treatment without a proven clinical benefit, and the 21-gene risk score is now widely used in clinical practice.
In non–small cell lung cancer, expression of programmed cell death ligand 1 (PD-L1) has been utilized as a biomarker to select patients for targeted therapy with pembrolizumab, a monoclonal antibody against programmed cell death protein 1. In the KEYNOTE-024 study, PD-L1 expression was quantified by immunohistochemistry using a commercially available test. Previously untreated advanced non–small cell lung cancer patients with at least 50% of tumor cells expressing PD-L1 and without 2 specific gene mutations were randomized to receive pembrolizumab or a platinum-based chemotherapy of the investigator’s choice. Median progression-free survival was significantly longer in the pembrolizumab group than in the chemotherapy group (10.3 months versus 6.0 months). Overall survival was also significantly longer in the pembrolizumab group (6). The indications for prescribing pembrolizumab include measurement of PD-L1 expression, underscoring the importance of this biomarker in directing therapy (7). A more recent clinical trial, KEYNOTE-042, has decreased the threshold of the tumor proportion score to at least 1% and shown encouraging results for treatment of patients with less expression of PD-L1 using targeted immunotherapy with pembrolizumab (8).
Although tissue-based biomarkers have demonstrated utility in certain clinical applications, the invasive nature of acquiring tissue limits widespread adoption for all potential biomarker applications. For example, the ability to monitor the effect of treatment over the course of therapy is limited by the frequency of tissue acquisition. Tissue sampling of limited sites of disease may fail to characterize the heterogeneity of a patient’s disease burden, potentially missing sites of disease that would ultimately drive progression. The noninvasive nature of imaging-based biomarkers—such as those obtained with positron emission tomography (PET)—overcomes several of the shortcomings of tissue-based biomarkers and enables serial measurement of the entire burden of disease. However, unlike tissue, where several processes can be measured (e.g., Oncotype DX is a 21-gene assay) on the same sample, image-based biomarkers are limited to the number of processes measured with a single radiotracer. Imaging also necessitates specialized scanners to image each patient, whereas tissue may be sent to a specialized laboratory for processing (1). With distinct strengths, tissue and imaging-based biomarkers have potential to complement each other to benefit the overall care of the patient.
Imaging the early steps of glycolysis with the glucose analog 18F-fluorodeoxyglucose (FDG) dominates current clinical PET imaging. As part of routine clinical care, FDG PET is used to stage numerous malignancies and monitor response to therapy (9). New research, though, has spurred the development of novel PET probes with expanded capabilities as imaging biomarkers. New probes can identify the presence of a therapeutic target to tailor the selection of individual cancer therapy and monitor response to targeted therapy. By the very nature of the modality, PET imaging captures regional heterogeneity in these targets (3).
Biomarkers may be incorporated into each aspect of clinical cancer care, including both diagnosis and treatment. Tasks include assessing risk and screening patients for disease, detecting and localizing disease, predicting outcome and response to specific treatments, assessing treatment response, and monitoring recurrence after successful treatment (10). Some biomarkers, such as pharmacokinetic and pharmacodynamic markers, may also be utilized to facilitate drug development (11). The testing characteristics of each biomarker—sensitivity, specificity, and cost—must be optimized for each application and tailored to the population and disease being studied (10).
Leveraging the inherent advantages of PET imaging, molecular imaging biomarkers have been incorporated into oncology primarily as prognostic, predictive, and pharmacodynamic/response markers (1,12,13). Below, we will discuss examples of imaging biomarkers in clinical trials using this task-specific framework.
In the context of clinical trial design, imaging biomarkers can be incorporated in an integrated or integral role. Integrated biomarker data are acquired in parallel with treatment study data but are not used to influence or direct treatment. Rather, such data are collected to test the accuracy and utility of the biomarker to inform future research without impacting the treatment of the patient in a current trial. In contrast, integral biomarkers directly influence the course of patients in a clinical trial. Integral biomarkers may be used to inform patient eligibility, stratify patients, and select therapy (12,14). An integrated biomarker with promise may be advanced into future clinical trials as an integral biomarker with the ultimate goal of directing patient care. Given this natural progression, most published research to date has studied integrated imaging biomarkers, though some established biomarkers have found widespread clinical acceptance. For example, interim FDG PET has been studied to direct lymphoma treatment, enabling modification of therapy early in the course of therapy (15), as discussed later in this article.
Prognostic biomarkers quantify the aggressiveness of a patient’s disease and the likelihood of mortality secondary to disease. In theory, these measures are independent of therapy, indicating an intrinsic characteristic of the disease (1). Ideally, studies of prognostic biomarkers should prospectively follow patients over the course of their disease. However, these studies are often retrospective, with the frequent use of specialized statistical methods to account for varied time of follow-up and potential confounding factors (16).
The prognosis of patients with thyroid cancer varies widely, ranging from an indolent disease to an aggressive disease with resultant mortality. Even within a subset of patients with metastatic disease, variability exists, with some patients surviving for decades or more. To better characterize these patients, FDG PET was studied as a prognostic factor in a retrospective review. Although many factors correlated with survival in a univariate analysis, only age and FDG PET findings, including whether disease was FDG-positive or -negative, remained significant. FDG positivity portended a poorer prognosis. These results suggest that assessing tumor glycolysis through measurement by FDG PET can identify tumors with an inherently more aggressive tumor biology and in predicting survival (17). As such, more aggressive treatment may be selected for patients with FDG-avid metastases, matching the aggressiveness of the treatment to that of the tumor.
The ability of magnetic resonance imaging and PET biomarkers to predict survival in glioblastoma was studied in the ACRIN 6684 clinical trial. Glioblastoma patients have a poor prognosis. Abnormal tumor vascularity leading to tissue hypoxia is thought to contribute to this aggressive phenotype. To interrogate this underlying biology, measurement of blood flow using magnetic resonance imaging and of tissue hypoxia using a PET imaging agent was studied as prognostic biomarkers in a prospective multicenter clinical trial (18). 18F-fluoromisonidazole had been previously validated as a marker of tissue hypoxia in viable cells in numerous prior studies involving both animals and humans (19). Both magnetic resonance imaging and PET markers demonstrated the ability to predict survival in patients with newly diagnosed glioblastoma. Treatment was not specified in this study; radiation and temozolomide were received by most patients, although some also received additional therapy as part of a clinical trial. In a receiver-operating-characteristic curve analysis, the peak and maximum standardized uptake values for 18F-fluoromisonidazole strongly predicted survival at 1 year, these being measures easily obtained on routine clinical PET imaging. Such prognostic information could be utilized to match treatment to disease aggressiveness, noting the heterogeneity of treatment in this study. Moreover, a measure of tissue hypoxia could be used to select patients for therapy and to guide therapy (18). As such, 18F-fluoromisonidazole may also serve as a predictive biomarker, as is discussed next.
Predictive biomarkers measure a biological characteristic that predicts the efficacy of a certain treatment. For instance, a PET measure of drug-target expression may serve as a biomarker for treatment efficacy with the paired targeted agent. As such, predictive biomarkers can select patients for targeted treatments, matching the actual treatment to the tumor biology. This represents a paradigm slightly different from that with prognostic biomarkers, which allow selection of only the aggressiveness of treatment, not the actual treatment (1). Biomarkers, though, may often have both simultaneous prognostic and predictive capabilities. For example, thyroid cancer metastases with FDG uptake have been shown to respond poorly to high-dose radioactive iodine (20). FDG uptake in thyroid cancer metastases is an indicator of both a poor prognosis and futility of treatment with radioactive iodine.
In breast cancer treatment, both estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) expression have been studied as predictive biomarkers, with paired targeted treatments available for both receptors. Decades of work have established the PET agent 18F-16α-fluoroestradiol (FES) as a marker of tumor ER expression, now FDA approved for breast cancer (21). An example of an FES PET scan in a woman with breast cancer is shown in Figure 1. In a sample of postmenopausal women with locally advanced, recurrent, or metastatic ER-positive breast cancer, baseline uptake of FES was greater in patients who responded to tamoxifen, a selective ER modulator, than in nonresponders (mean SUV of 4.3 versus 1.8, respectively), suggesting FES to be a predictive biomarker for targeted ER therapy (22). In a population of heavily pretreated metastatic breast cancer patients, an SUV threshold of 1.5 demonstrated an ability to discriminate between responders and nonresponders. None of the 15 patients with an SUV of less than 1.5 responded to endocrine treatment; 11 of 32 patients with an SUV of more than 1.5 responded. These results suggest futility in using endocrine therapy on patients with a low uptake of FES, although uptake of FES certainly does not guarantee a response (23). Another trial studied patients with acquired resistance of ER-positive advanced breast cancer to endocrine treatment. This trial studied FES as a predictive marker in selecting patients for estradiol therapy, noting success seen with additive estrogen therapy in patients extensively pretreated with antiestrogen therapy. Patients with low FES uptake were unlikely to respond to estradiol therapy (negative predictive value of 80%) (24). Similarly, imaging of the HER2 receptor with 89Zr-trastuzumab has also advanced into clinical trials, as discussed below.
|Figure 1. PET imaging of estrogen receptor-positive metastatic breast cancer. (A) PET, CT, and fused axial images from 18F-FDG PET/CT showing uptake in sternal metastasis in patient with metastatic breast cancer. (B) PET, CT, and fused axial images from 18F-FES PET/CT at the same level demonstrate uptake reflecting estrogen receptor expression in this osseous metastasis.|
Non-invasive molecular imaging of early (pharmacodynamic response) to therapy may enable early prediction of response to therapy. As molecular changes in tumor biology as queried with PET precede anatomic changes, PET imaging biomarkers may enable earlier assessment than an anatomic imaging modality such as CT (16). Early assessment can guide therapy, possibly allowing discontinuation of a futile therapy or continuation of a therapy with an encouraging early response. Moreover, given the complex interrelationships between cellular pathways, a single PET tracer can measure the early response to many therapies. FDG has proved successful in this regard; 2 examples with different treatment regimens are given below.
In the Neo-ALTTO trial, FDG PET was studied as a biomarker for early prediction of response to neoadjuvant lapatinib, trastuzumab, and their combination in HER2-positive breast cancer patients. Metabolic response on PET at 2 weeks correlated with PET response at 6 weeks. Rates of pathologic complete response were twice as high for patients with a PET response as for those without a response (25). In ER-negative, HER2-positive breast cancer patients, the TBCRC026 trial studied FDG PET as an early marker of pathologic complete response to pertuzumab and trastuzumab. A decrease in maximum SUV corrected for lean body mass at 15 days after initiation of neoadjuvant pertuzumab and trastuzumab, compared with baseline, predicted a pathologic complete response (26). These 2 landmark studies suggest that assessment of early metabolic response with FDG can predict a pathologic complete response, a marker that has prognostic implications. Such an early biomarker might allow tailoring of treatment on a patient-by-patient basis.
In prostate cancer, 18F-fluoride PET was used an early indicator of response to dasatinib and correlated with progression-free survival in the ACRIN 6687 clinical trial. As a quantitative measure of bone formation and turnover, 18F-fluoride offers advantages over anatomic imaging, bone scintigraphy, and FDG PET for imaging osteoblastic disease. Patients were scanned at baseline and 12 weeks after initiation of dasatinib, a tyrosine kinase inhibitor with effects on bone. A significant decrease in maximum SUV was seen in bone metastases but not in normal bone, suggesting that dasatinib is specific for bone metastases. Furthermore, changes in 18F-fluoride uptake demonstrated a borderline correlation with progression-free survival (27). As with FDG, 18F-fluoride demonstrated an ability to detect early treatment changes, suggesting a possible role for prediction of outcomes.
On the basis of encouraging results from separate key studies of 89Zr-trastuzumab PET and FDG PET in HER2-positive breast cancer, the ZEPHIR study combined these biomarkers in a single study to identify patients unlikely to respond to trastuzumab emtansine, a HER2-targeted antibody-drug conjugate. A pretreatment 89Zr-trastuzumab PET scan was utilized as a predictive biomarker; FDG PET was performed at baseline and after 1 cycle of trastuzumab as an early pharmacodynamic/response marker. Patients were placed into 4 groups based on the proportion of FDG-avid tumor burden demonstrating 89Zr-trastuzumab uptake. Response to FDG PET was dichotomized into responders and nonresponders. The authors hypothesized that the combination of these markers would better capture disease heterogeneity and allow better prediction of response to targeted therapy. When 89Zr-trastuzumab and FDG PET were combined, both a 100% positive predictive value and a 100% negative predictive value for anatomic response were achieved, greater than either PET scan individually (28). Combining a biomarker of target expression with a biomarker of early response proved synergistic, perhaps establishing a new paradigm for future studies.
The natural progression of advancing an integrated biomarker to an integral biomarker in clinical trials has led to numerous promising integrated biomarkers, with several examples discussed above. Naturally, fewer biomarkers have been studied in an integral manner, with the use of FDG PET in lymphoma being one of the most robust and extensively studied in an integral fashion. FDG PET/CT has gained widespread clinical acceptance for staging and end-of-treatment response; the Lugano criteria and Deauville score have been embraced for these assessments (29). In addition, early PET/CT after the initiation of chemotherapy has been leveraged as an early prognostic indicator in some types of lymphoma, with several trials studying PET as an imaging biomarker in a response-adapted treatment trial. A randomized trial published in 2017 studied early FDG PET as an integral marker in previously untreated stage I and II Hodgkin lymphoma patients. FDG PET was performed after 2 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). In the standard arm, all patients continued ABVD followed by involved-node radiotherapy, without consideration of early PET results. In the experimental arm, PET-positive patients had escalated therapy and involved-node radiotherapy; PET-negative patients received ABVD only, not involved-node radiotherapy. In PET-positive patients, 5-year progression-free survival was greater for the escalated therapy than the standard therapy, which did not consider the early PET findings. Noninferiority of treatment with only ABVD in the PET-negative patients was not shown (30). Early evaluation with FDG PET as an integral imaging biomarker proved useful in PET-positive patients, underscoring the utility of early metabolic imaging in guiding cancer treatment.
Molecular imaging offers an unparalleled opportunity to noninvasively interrogate a biological process over the entire patient. With such detailed information, cancer treatment may be tailored to match a patient’s disease characteristics. Molecular imaging biomarkers, however, must be carefully integrated into appropriate imaging–treatment paradigms. Such biomarkers may be utilized for a variety of tasks—from prognosis to patient selection to measurement of therapeutic response—with the biological characteristic queried, informing its proper utilization. Representative examples of biomarkers currently in clinical development have been discussed in this article. Several of these integrated biomarkers, including recently approved agents such as FES, are poised to move into the clinic, providing new tools to physicians to better care for patients. Other biomarkers are primed to move into more advanced clinical trials. Although the examples in this review focus on directing chemotherapy for treatment of cancer, biomarkers may also be utilized to direct targeted radionuclide therapy. For instance, 68Ga-DOTATATE PET serves as a companion diagnostic agent to identify somatostatin-positive disease for treatment with 177Lu-DOTATATE, which has revolutionized modern treatment of neuroendocrine tumors (31).
Several factors, though, temper the momentum for advancing imaging biomarkers into routine clinical practice. Limited health-care and research resources, combined with the logistical challenges of translating imaging biomarkers from the laboratory to the clinic, require careful coordination and forethought (32). With properly planned and executed studies, the true power of imaging biomarkers to advance precision medicine can be revealed.
Note: This article was originally submitted in April 2019.
|Katherine Zukotynski, MD, PhD, FRCPC|
Dear Friends and Colleagues,
From where does inner strength derive? For some of us, drinking coffee watching the sun rise over the ocean, or perhaps a daily jog, keeps us sane. For some, it is family, friends or colleagues. Others require chocolate or sweets of any kind or might opt for meditation in a quiet room, if they can find one. My 7-year-old daughter has an imaginary tree house. From what I can tell, life is whatever you want it to be in the tree house. She has a room for toys, another for animals, and another dedicated entirely to summer…and she can go there whenever she needs to get away.
For many of us, the last year has brought tales of human strength and frailty. After all, times of stress tend to bring out the worst and the best within us. For myself, looking back, I will forever remember the family who moved their elderly dependent into a retirement home knowing there was COVID-19 lurking there already. Then again, I will also remember the woman, a wife of more than 60 years, who managed to be admitted to the same room in the hospital as her husband, on his 85th birthday, so they could convalesce together. I suspect this was the only way they could have been together, in the hospital, while COVID-19 raged around them. I remember countless research protocols forcibly stopped and wonder what impact this will have on our data going forward.
I also remember the patchwork of hospital leadership resulting in extreme variations in clinical practice. To wit, the same cardiac stress test performed on an outpatient post negative COVID-19 screening survey at one hospital might be done with staff garbed in a mask, face shield, gloves, and gown versus another hospital, within easy driving distance, where no protective equipment was worn or, perhaps, even available. Some of us learned to cut hair, others discovered Zoom bombing. There were virtual concerts, educational talks and ballets open to all. We made banana bread and ate it watching Webcam footage of events with few or no spectators allowed in. Commute times to work become negligible, and the price of gas plummeted. Our children learned from home, and convocations occurred remotely. We discovered that we no longer needed to explain the concept of social distancing to patients receiving radioiodine therapy. They understood it already!
As might be expected, our newsletter features articles on providing nuclear medicine services during the time of COVID-19 and incidental findings to watch for. Of course, science knows no bounds, and advances in radiopharmaceuticals and imaging continue. So, we also discuss PSMA-PET/MR, and our lead article is on molecular imaging biomarkers and their role in precision medicine, an area of ongoing research. As before, there is CE credit attached.
This newsletter has been in the works for a very long time, and I am deeply grateful to all who carried it past the finish line. In particular, I would like to thank Eleanor Gillis, David Mankoff, Austin Pantel, Liza Lindenberg, Aloyse Fourquet, Baris Turkbey, Esther Mena, Peter Choyke, Medhat Osman, Shana Elman, Twyla Bartel, the SNMMI staff, and members of the PET CoE and Newsletter Editorial Board who made it possible. Further, my sincere congratulations go to Dr. Simon Cherry and Dr. Ramsey Bedawi on winning the Valk award in 2020 and to Dr. Rodney Hicks on winning the Valk award in 2021, our greatest honor.
We are in the home stretch for the SNMMI Annual Meeting, a virtual event that will be held in July. Additional sessions will be held throughout the year as part of our ongoing online webinar program. We hope you will be able to join us!
So then, how do I find my inner strength? I think of my favourite things: loons calling on a remote lake, skiing in the Rockies, the sun shining warmly upon my face, bright flowers of any kind and the colleagues, friends and family who have walked the trail with me. Then I look for a silver lining and try to find it no matter how faint it may be. With time, the mind tends to dull the bad and brighten the good. I expect we shall see each other again, one day soon and those of you who have lightened the load have made all the difference. Thank you!
I will conclude with a well-worn poem. I hope it brings to you the same feelings it brings to me.
If you can keep your head when all about you
Are losing theirs and blaming it on you;
If you can trust yourself when all men doubt you,
But make allowance for their doubting too;
If you can wait and not be tired by waiting,
Or, being lied about, don’t deal in lies,
Or, being hated, don’t give way to hating,
And yet don’t look too good, nor talk too wise;
If you can dream—and not make dreams your master;
If you can think—and not make thoughts your aim;
If you can meet with triumph and disaster
And treat those two imposters just the same;
If you can bear to hear the truth you’ve spoken
Twisted by knaves to make a trap for fools,
Or watch the things you gave your life to broken,
And stoop and build ’em up with wornout tools;
If you can make one heap of all your winnings
And risk it on one turn of pitch-and-toss,
And lose, and start again at your beginnings
And never breath a word about your loss;
If you can force your heart and nerve and sinew
To serve your turn long after they are gone,
And so hold on when there is nothing in you
Except the Will which says to them: “Hold on”;
If you can talk with crowds and keep your virtue,
Or walk with kings—nor lose the common touch;
If neither foes nor loving friends can hurt you;
If all men count with you, but none too much;
If you can fill the unforgiving minute
With sixty seconds’ worth of distance run -
Yours is the Earth and everything that’s in it,
And—which is more—you’ll be a Man my son!
Center for Cancer Research, National Cancer Institute.
Worldwide, prostate cancer is the second most common malignancy. Advanced imaging can play a significant role in detecting this disease earlier, when it is still curable. PET is beneficial in providing biological information about cancer and has good sensitivity and high specificity for residual or recurrent prostate tumor.
FDA-approved 18F-fluciclovine and novel PSMA targeting agents are the most widely used PET tracers in imaging of prostate cancer. Multiparametric MRI is helpful in diagnosing and characterizing localized prostate cancers and directing MR-guided fusion biopsies. Combined, the strengths of both modalities can enhance diagnostic capabilities. Clinically introduced in 2010, hybrid PET/MR could be useful in prostate cancer evaluation, but many institutions lack this novel technology and may not have the substantial resources needed for investment. A larger number of facilities, however, do have stand-alone MRI scanners and PET/CT cameras that could be jointly employed to provide similar value.
Many commercial viewing platforms have the technical capability to fuse PET and MR images. Combining functional PET and morphologic MR images requires image processing software and several simple steps. We use MIM Software in our department, and the key is to register the PET with the CT and then register the CT with the MRI to achieve PET/MR registration. Similar integration methods can be found with other vendors, and this software-based registration offers greater imaging flexibility for patients.
In the setting of high-risk localized and biochemically recurrent prostate cancer, the advantages of PET/MR are clear. PET is of limited value in small lesions, because the inherent spatial resolution constraints and tumor localization within the prostate can be challenging on CT. The prostate gland and seminal vesicles are difficult to distinguish from muscles, ligaments, and the urinary bladder or rectal wall on CT. MRI, conversely, has excellent contrast resolution in the prostate and surrounding tissues, allowing many different structures—such as the peripheral zone and transition zone of the prostate gland, urethra, prostate capsule and seminal vesicles—to be readily identified. Merging PET and MR images brings the best of both modalities together for improved tumor detection.
At our institution, we are currently enrolling under clinical trials identifier NCT03181867 to study a PSMA-based PET agent, 18F-DCFPyL, in high-risk and recurrent prostate cancer. Clinical trial participants are typically imaged first on a 3T MRI with endorectal coil for pelvic multiparametric sequences that include diffusion weighted MRI (apparent diffusion coefficient [ADC] maps and high b value [2000s/mm2] DW MRI) and dynamic contrast-enhanced (DCE) images. The same day or shortly thereafter, participants are injected with approximately 8 mCi of 18F-DCFPyL and imaged 2 hours later on a PET/CT with time-of-flight reconstruction. Results are encouraging and suggest compelling applications in prostate cancer to influence clinical practice. Specifically, it can provide a more certain map of localized tumor to aid targeted biopsies and therapy, increasing tumor detection in biochemical recurrence and improving staging of metastatic disease.
|Images of an 81-year-old man with prostate cancer, Gleason score 7(4+3), stage T2a at diagnosis. He underwent stereotactic body radiation therapy (SBRT) 5 months after diagnosis and achieved a PSA nadir of 1.4 ng/mL. He was imaged on study approximately 7.5 years after definitive therapy with a rising PSA of 10.37 ng/mL. Combining PET and MR images enhanced detection certainty. Focal uptake on PET and MR illustrate a midline to right mid-base peripheral zone lesion in the prostate.|
Department of Radiology, St. Louis University, St. Louis, MO.
On March 11, 2020, the World Health Organization declared COVID-19 a pandemic. Since then, there has been a staggering number of positive cases and related deaths worldwide. The United States alone reported just over 500,000 losing their lives by the end of February 2021. Health care workers continue to face unprecedented challenges. Furthermore, local, regional, national, and international guidelines continue to evolve. We, in the nuclear medicine community, are trying to keep up with these fast-paced changes.
How can we continue to provide nuclear medicine services while minimizing exposure to all involved, from staff to patients? The following presents some general recommendations to the nuclear medicine community, with a focus on PET. As always, the applicability of these recommendations should be tailored to each individual site.
Schedule Triage: All ordered studies should be triaged into nonessential and essential categories. Nonessential studies, such as elective and research studies, can be postponed or cancelled if needed. For studies deemed essential, patients should be screened for known or suspected COVID-19 infection. If there is no apparent risk for COVID-19 or if the patient has been tested negative for the virus, the study may proceed. For patients with suspected COVID-19, nuclear medicine interventions should await test results. If the test results are positive, the infectious disease team should be contacted to establish the best method to proceed.
Securing Remote Access: Remote review and reporting should be made available for reading physicians. Teleconferences for teaching, multidisciplinary conferences, and virtual consultation for patients should be enabled.
Personal Protective Equipment (PPE): PPE should be available, and staff should be trained and re-trained on how and when to use it.
Cross-Training and Segregation: Cross-training and segregating staff into teams to help minimize exposure and ensure continued functionality of the service in case of actual exposure.
The waiting time for patients with known or suspected COVID-19 in the nuclear medicine department should be minimized, and these patients should remain in a dedicated room that is separate from other patients in as much as possible. All staff should use appropriate PPE.
Lung windows should be promptly reviewed, and any incidental findings that might suggest COVID-19 should be immediately reported and documented.
In addition to standard cleaning of surfaces, a special disinfection protocol should be enacted after a known COVID-19–positive case has been in the nuclear medicine department. Furthermore, a mechanism must be in place to follow up with all patients undergoing nuclear medicine examinations, including those with negative COVID-19 results. Since test results may become available later, contact tracing may be required. Staff members who had contact with a known or later-discovered COVID-19 positive case should be informed and closely monitored, and a consultation with the local employee health department is advised. Excellent examples of incidental findings of COVID-19 (with a focus on PET/CT) are included in the companion article in this newsletter presented by Drs. Shana Elman and Twyla Bartel.
An aside note: At our institution we now do V/Q scans with perfusion only, following the SNMMI guidance, and rely on perfusion-only imaging for pulmonary embolism (PE) diagnosis. We discuss this modification with the ordering physician prior to the study. Further, for patients with suspected or confirmed infection, following consultation and determining necessity/feasibility with the infectious disease team, studies are performed in a negative pressure room with adequate time between patients to minimize risk of exposure to subsequent patients and/or staff. We have found that using hybrid perfusion single-photon emission computed tomography/computed tomography (SPECT/CT) for PE is a comparable alternative to the traditional V/Q scan with multiple benefits. SPECT/CT has demonstrated better certainty in identifying perfusion defects compared to planar perfusion imaging alone. The total radiation exposure to the patient is nearly the same; however, there is a significant reduction in the total exam duration, technologist exposure time to radiation and virus, reliance on patient cooperation, need for a repeat ventilation, and improved accuracy. We have also found that the benefits of additional anatomical localization of perfusion defects, parenchymal disease, and incidental findings are an advantage that should not be overlooked.
SNMMI Statement: COVID-19 and Ventilation/Perfusion (V/Q) Lung Studies
SNMMI Statement: The Effect of COVID-19 Vaccination on FDG PET/CT
1Division of Nuclear Medicine, University of New Mexico Medical Center. 2Global Advanced Imaging, PLLC.
Over the past year, our practices have evolved as we try to better understand the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the disease that it causes, COVID-19. Our departments have followed many of the steps outlined in the companion article in this newsletter by Medhat Osman, to ensure we can provide nuclear medicine services in a way that is safe for our patients and staff. For outpatient services in particular, we screen patients for signs, symptoms, and risk factors for COVID-19 infection often by phone prior to the appointment, upon entering the building where imaging is performed, upon checking in, and often again by our technologists. Despite our best attempts, these screening processes are imperfect, as many people with COVID-19 infection may be asymptomatic. In addition, patients may misinterpret symptoms they are having as unrelated to COVID-19 infection and exclude details, may misinterpret screening questions, or may not completely understand instructions.
Figure 1 demonstrates a patient imaged at our Cancer Center for routine imaging of pancreatic neuroendocrine tumor. He did not meet criteria for COVID-19 testing by phone or at multiple checkpoints in person, including having his temperature checked upon entering the building. However, his CT showed new patchy and consolidative ground-glass opacities. Luckily, our radiologist quickly notified the referring clinician and the patient was still in clinic. Upon further questioning by the referring provider, the patient again denied high risk exposure or risk factors, but he endorsed a cough and some slight fatigue, which he thought was related to allergies. Per our institutional policy for patients under investigation (PUI), the patient and his wife immediately reported to the designated COVID-19 testing area. After testing, they were given instructions for self-quarantine. Within 24 hours, the Coronavirus PCR results for the patient and his wife came back as positive.
As another example of the imperfections of the screening process, we were contacted by the Cancer Center to notify us that a patient had a pending COVID-19 test and his bone scan should be rescheduled. Unfortunately, the patient had already completed his bone scan prior to the call. Thankfully, his test came back negative the next day. When the patient was later asked why he went to the appointment despite being told to quarantine and why he did not mention his pending COVID-19 test when he checked in for his bone scan, the patient said he didn’t realize the quarantine instructions included doctor’s appointments. We have also encountered patients who have not mentioned symptoms or possible exposures because they are anxious to get their imaging done and worried that endorsing symptoms or risk factors may further delay an imaging exam that had already been postponed.
Imperfections in the screening process are not limited to the outpatient setting. As the prevalence of COVID-19 increased in our local population, it was not uncommon to encounter a patient admitted for management of trauma or other medical problem (e.g., pancreatitis, stroke, etc.) who also tested positive for COVID-19 infection. Figure 2 shows an inpatient, admitted for management of a stroke, who had a prior CT showing a suspicious solitary pulmonary nodule (SPN). During her inpatient stay, she was scheduled for FDG PET/CT to follow up the SPN. The patient had a COVID-19 PCR test on admission, but rapid results were reserved for patients with known positive contacts or symptoms. Accordingly, her test results took 4 days to return, at which time she was in our PET suite getting her PET/CT. The positive COVID-19 test results did not surprise us, given the appearance of intensely hypermetabolic ground-glass opacities throughout the lungs (obscuring the SPN for which the PET/CT was requested).
Multiple radiological societies have stated that CT should not be relied upon as a diagnostic/screening tool for COVID-19. However, given the imperfections of screening and the possibility that carriers of COVID-19 infection may be completely asymptomatic, it is it is important to be aware of the typical CT findings that can be incidentally seen in COVID-19 infection, especially if you practice in an area with a high prevalence of COVID-19 infection. While CT is not specific for COVID-19 pneumonia, it has shown a high diagnostic sensitivity; therefore, typical findings should be promptly reported to the referring provider, and subsequent action should be taken based on your institutional policy.
RSNA has released an expert consensus statement on reporting chest CT findings related to COVID-19 that highlights the common CT findings and how to report them (https://pubs.rsna.org/doi/pdf/10.1148/ryct.2020200152). At our institution, after discussion with our pulmonologists/critical care physicians, we elected to describe findings that may be suggestive of COVID-19 pneumonia as concerning for “viral” pneumonia, if a COVID-19 test result was not yet available. Any unexpected findings typical of COVID-19 infection are immediately reported to the ordering provider, and we make clear to the provider by phone that although nonspecific, the findings are typical for COVID-19 infection and further investigation may be warranted (e.g., RT-PCR testing if available).
Although all viral pneumonias have overlapping findings on a chest CT, features that tend to be more common in COVID-19 associated pneumonia have now been extensively described. In a study directly comparing chest CT patterns of COVID-19 and other viral pneumonias, COVID-19 pneumonia was statistically more likely to have a peripheral distribution (80% vs. 57%), ground-glass opacity (91% vs. 68%), fine reticular opacity (56% vs. 22%), and vascular thickening (59% vs. 22%), but less likely to have a central+peripheral distribution (14.% vs. 35%), pleural effusion (4.1 vs. 39%) and lymphadenopathy (2.7% vs. 10.2%) (https://pubs.rsna.org/doi/full/10.1148/radiol.2020200823). Of particular note, bronchial wall thickening, mucoid impactions, and tree-in-bud or centrilobular nodules are not typically observed in COVID-19 infection, although seen commonly in other infections. In a patient with known COVID-19 pneumonia, the presence of these less-common features should raise the possibility of superinfection by other infectious etiologies.
Multiple papers have also recently come out illustrating the appearance of COVID-19 on PET/CT or SPECT/CT, often incidentally identified, particularly in areas with higher prevalence of positive cases. In the April 1, 2020 issue of JNM, Albano et al. reported that six out of sixty-five asymptomatic patients getting a PET/CT and one of twelve patients with a radioiodine SPECT/CT showed findings of interstitial pneumonia on the CT portion of the exam. Of those seven, five of the patients were confirmed to have COVID-19; the remaining two did not receive immediate testing but underwent quarantine and careful monitoring (http://jnm.snmjournals.org/content/early/2020/04/01/jnumed.120.246256.full.pdf+html). Colandrea and colleagues subsequently described 5 patients identified over a 3-week period who were asymptomatic, but also had PET/CT findings suspicious for COVID-19; later confirmed with RT-PCR (https://europepmc.org/article/ppr/ppr151049).
Variable FDG uptake can be seen corresponding to the CT abnormalities. Two incidentally discovered cases of COVID-19 infection shown above had no significant FDG uptake corresponding to nodular ground-glass opacities (Figure 3). Another case in a patient with known COVID-19 infection demonstrates moderate FDG uptake corresponding to multifocal ground-glass opacities (Figure 4).
Although nuclear medicine procedures are unlikely to play a role in the primary diagnosis of COVID-19, alerting clinicians to incidental detection of the disease in asymptomatic patients undergoing scans for other indications has potentially relevant implications for further management. As described in Dr. Osman’s article in this newsletter, when lungs are included in the imaged field-of-view, whether on CT, PET-CT, or SPECT-CT, the lung window should be promptly reviewed and any incidental findings that might suggest COVID-19 should be immediately reported and documented. Tulchinsky et al. suggests augmenting visualization of the lung parenchyma on non-breathhold localizing CTs by using edge enhancement (https://journals.lww.com/nuclearmed/Abstract/9000/Incidental_CT_Findings_Suspicious_for_Covid_19.96724.aspx).
Particularly in oncologic imaging, it is also important to consider other etiologies that may demonstrate findings on CT similar to COVID-19 pneumonia, including treatment-related complications (such as radiation or drug-related pneumonitis/organizing pneumonia), other types of infection (particularly other viral pneumonias as described above), vasculitis, edema, and pulmonary hemorrhage. Examples of such cases are shown in Figure 5a-d.
New Radiotracer Safe and Effective for Imaging Early Rheumatoid Arthritis
New research shows that a novel positron emission tomography (PET) tracer that targets inflammation is safe and can clearly identify early stages of rheumatoid arthritis. The promising PET tracer, 68Ga-DOTA-Siglec-9, rapidly clears from blood circulation, has a low radiation dose, and can be easily produced. This first-in-human study was published in the April issue of The Journal of Nuclear Medicine.
Inflammation is a significant part of several chronic diseases, including rheumatoid arthritis and its related issues. While PET imaging with 18F-FDG is a valuable tool for the diagnosis and monitoring of the effects of treatments, it is not specific enough to assess inflammation.
“It’s important to detect inflammation early so that patients can receive the best treatment,” said Anne Roivainen, PhD, professor of preclinical imaging and drug research at Turku PET Centre at the University of Turku and Turku University Hospital in Finland. “Our institution has worked for several years to develop an imaging agent that targets areas of inflammation, and in this study, tested its effectiveness in humans for the first time.”
To evaluate the radiotracer’s safety and biodistribution characteristics, six healthy study participants underwent whole body 68Ga-DOTA-Siglec-9 PET/computed tomography scans. 68Ga-DOTA-Siglec-9 was well-tolerated and cleared quickly from the blood, and its radiation dose was similar to other 68Ga tracers. In one additional study participant with rheumatoid arthritis, the tracer was able to clearly detect joints with arthritis.
“We have proven that the characteristics of 68Ga-DOTA-Siglec-9 are favorable for use in patient imaging studies,” remarked Roivainen. “Future studies will clarify whether 68Ga-DOTA-Siglec-9 PET imaging has the potential to detect other inflammatory diseases early. It could also help to evaluate the effectiveness of treatments and promptly identify patients who are unlikely respond to therapy.”
|Figure: The inflamed joints of a patient with rheumatoid arthritis are clearly visible in the PET/CT images with the novel 68Ga-DOTA-Siglec-9 radiopharmaceutical.|
The authors of "First-in-Humans Study of 68Ga-DOTA-Siglec-9, a PET Ligand Targeting Vascular Adhesion Protein 1" include Riikka Viitanen, Olli Moisio, Xiang-Guo Li, Vesa Oikonen and Helena Virtanen, Turku PET Centre, University of Turku, Turku, Finland; Petteri Lankinen, Department of Orthopaedics and Traumatology, Turku University Hospital and University of Turku, Turku, Finland, and Turku PET Centre, Turku University Hospital, Turku, Finland; Mikko Koivumäki, Turku PET Centre, Turku University Hospital, Turku, Finland; Sami Suilamo, Department of Medical Physics, Turku University Hospital, Turku, Finland, and Department of Oncology and Radiotherapy, Turku University Hospital, Turku, Finland; Tula Tolvanen, Turku PET Centre, Turku University Hospital, Turku, Finland, and Department of Medical Physics, Turku University Hospital, Turku, Finland; Kirsi Taimen, Markku Mali, Ilpo Koskivirta and Laura Pirilä, Department of Rheumatology and Clinical Immunology, Division of Medicine, Turku University Hospital, Turku, Finland; Ia Kohonen, Department of Radiology, Turku University Hospital, Turku, Finland; Kristiina Santalahti and Sirpa Jalkanen, MediCity Research Laboratory, University of Turku, Turku, Finland; Anu Autio, Turku PET Centre, University of Turku, Turku, Finland, and MediCity Research Laboratory, University of Turku, Turku, Finland; Antti Saraste, Turku PET Centre, University of Turku, Turku, Finland, Turku PET Centre, Turku University Hospital, Turku, Finland, and Heart Center, Turku University Hospital, Turku, Finland; Pirjo Nuutila, Juhani Knuuti and Anne Roivainen, Turku PET Centre, University of Turku, Turku, Finland, and Turku PET Centre, Turku University Hospital, Turku, Finland.
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May 27, 2021—12:00-1:00 pm
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