Cancer Diagnostics and Molecular Pathology
Impact on Patient Management of [18F]-Fluorodeoxyglucose-Positron Emission Tomography (PET) Used for Cancer Diagnosis: Analysis of Data From the National Oncologic PET Registry RATHAN M. SUBRAMANIAM,a,b ANTHONY F. SHIELDS,c ARCHANA SACHEDINA,d LUCY HANNA,e FENGHAI DUAN,e BARRY A. SIEGEL,d,f BRUCE E. HILLNERg a Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; bUniversity of Texas Southwestern Medical Center, Dallas,Texas, USA; cKarmanos Cancer Institute, Wayne State University, Detroit, Michigan, USA; dDivision of Nuclear Medicine, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri, USA; eCenter for Statistical Sciences, Brown University, Providence, Rhode Island, USA; fSiteman Cancer Center,Washington University School of Medicine, St. Louis, Missouri, USA; gDepartment of Internal Medicine and the Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA
Disclosures of potential conflicts of interest may be found at the end of this article.
Key Words. Cancer diagnosis x Cancer of unknown primary origin x Paraneoplastic syndrome x National Oncologic PET Registry
ABSTRACT Introduction. Weassessedtheimpactof[18F]-fluorodeoxyglucose (FDG)-positron emission tomography (PET) on intended managementofpatientsintheNational OncologicPETRegistry(NOPR)for three different diagnostic indications: (a) determining whether a suspicious lesion is cancer (Dx), (b) detecting an unknown primary tumor site when there is confirmed or strongly suspected metastatic disease (cancer of unknown primary origin [CUP]), and (c) detecting a primary tumor site when there is a presumed paraneoplastic syndrome (PNS). Methods. We reviewed a sample of randomly selected reports of NOPR subjects who underwent PET for Dx and CUP and all reports for PNSto find subjects foranalysis. For these studies, we evaluated the impact of PET on referring physicians’ intended management, based on their management plans reported before and after PET.
Results. Intended management was changed more frequently in the CUP group (43.1%) than in the Dx (23.9%) and PNS (25.4%) groups (CUP vs. Dx, p , .0001; PNS vs. Dx, p , .0001; CUP vs. PNS, p , .0002). Referring physicians reported that, in light of PET results, they were able to avoid further testing in approximately three-fourths of patients (71.8%–74.6%). At the time when the post-PET forms were completed, biopsies of suspicious sites had been performed in 21.2%, 32.4%, and 23.2%, respectively, of Dx, CUP, and PNS cases. Conclusion. Our analysis of NOPR data shows that PET appears to have a substantial impact on intended management when used for three common diagnostic indications. The Oncologist 2016;21:1079–1084
Implications for Practice: [18F]-fluorodeoxyglucose-positron emission tomography appears to have a substantial impact on intended management when used for three targeted diagnostic indications: (a) determining whether a suspicious lesion is cancer, (b) detecting an unknown primary tumor site in a patient with confirmed or strongly suspected metastatic disease, and (c) detecting a primary tumor site in a patient with a presumed paraneoplastic syndrome.
INTRODUCTION Positron emission tomography (PET)/computed tomography (CT) and PET alone with [18F]-fluorodeoxyglucose (FDG) are useful in a variety of common situations among patients with cancer, including staging for planning of initial treatment, detecting residual tumor after therapy, and detecting recurrent disease. PET is also helpful for several cancer diagnosis indications. These include determining whether a suspicious lesion is likely to be malignant (e.g., evaluation of a solitary pulmonary nodule) [1, 2] and assessing lesions with
indeterminate biopsy results or that are inaccessible for biopsy (so-called metabolic biopsy) [3, 4]; identifying the site of an unknown primary cancer in a patient with proven or strongly suspected metastatic disease [5–8]; and detecting an occult primary cancer in a patient with a suspected paraneoplastic syndrome [9–11]. The National Oncologic PET Registry (NOPR) was developed, under the sponsorship of the World Molecular Imaging Society (formerly the Academy of Molecular Imaging), to meet
Correspondence: Rathan M. Subramaniam, M.D., Ph.D., Department of Radiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas,Texas 75390, USA.Telephone: 214-645-2762; E-Mail: [email protected] Received September 13, 2015; accepted for publication May 12, 2016; published Online First on July 8, 2016. ©AlphaMed Press 1083-7159/2016/$20.00/0 http://dx.doi.org/ 10.1634/theoncologist.2015-0364
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the requirements of the Centers for Medicare & Medicaid Services (CMS) for coverage with evidence development (CED) of FDG-PET in Medicare beneficiaries with noncovered cancer types or indications. NOPR’s primary objective was to measure the impact of PET on referring physicians’ intended patient management by collecting questionnaire data before the PET scan and again after the PET results were available [12]. NOPR opened to accrual in May 2006. We have previously reported NOPR findings on the impact of PET on intended patient management for various cancer types and imaging indications. Overall, PET was associated with a change in intended management in about one third of cases, with minimal clinically important differences by cancer type, testing indication, or time period [13–15]. The use of PET for cancer diagnosis was explored in our initial publication of NOPR results [13], with the finding of a change from a nontreatment plan to a treatment plan, or vice versa, in 31.1% of 5,516 scans (representing 19.4% of all scans in the initial NOPR cohort). However, that initial publication did not separately assess the impact of PET for the three major diagnostic applications described above. The current report represents a more detailed analysis of NOPR data regarding the use of PET for cancer diagnosis.
METHODS NOPR Design and Workflow NOPR is a prospective data registry that collects information from the PET facility, from the physician requesting the PET scan, and from the interpreting physician’s PETreport. Detailed descriptions of NOPR operations, human subject protection procedures, and results for the impact of PET on physicians’ intended management were previously reported [12–15]. Both patient and referring physician consent were required for the research use of their data. The research conducted using NOPR data is registered as NCT00868582 at ClinicalTrials.gov. The questions completed by the referring physician on the prePET form and on the post-PET forms specific to the diagnostic indications are shown in the supplemental online Appendix.
Eligibility for Inclusion in the Analysis Set Between May 2006 and April 2009, data were collected for 132,946 scans performed at approximately 1,693 facilities. Consent from patients and referring physicians for use of the data for research purposes was obtained for 116,927 scans (88%), and 21,931 (18.7%) of these were performed for one of the three previously noted diagnostic indications: determining whether a suspicious lesion is cancer (Dx; n 5 14,072); detecting an unknown primary tumor site when there is confirmed or strongly suspected metastatic disease (CUP; n 5 6,966); and detecting a primary tumor site when there is a presumed paraneoplastic syndrome (PNS; n 5 893). The types of cancers in the diagnostic indications cohort included all those for which use of FDG-PET for diagnosis was covered by CMS only if the patient was enrolled in the NOPR during the study interval. The excluded types, therefore, were suspected breast, non-small cell lung, head and neck and esophageal cancers, lymphoma, and melanoma. Accordingly, the eligible population consisted of scans ordered to evaluate
patients suspectedofhaving oneoftheless frequent, noncovered cancer types. During our initial evaluation of data for scans ordered for these diagnostic indications, we became concerned that the imaging indication selected on the pre-PET form was incorrect in many instances. It seemed likely that “diagnosis” was selected on the pre-PET form in many instances when PET was being obtained to evaluate a suspicious lesion in a patient with a known cancer. Accordingly, we undertook a quality control analysis of a random sample of 200 cases (100 Dx and 100 CUP) in which we compared the recorded indication and the referring physician’s estimate of the patient’s summary stage on the pre-PET form with the description or documentation of the patient’s history and findings in the actual PETreport. As expected, based on our previous review of information included in NOPR PET reports [16], many of the reports contained insufficient information to determine if the selected indication was correct. Other reports clearly showed that the selected indication was likely incorrect. We determined, therefore, that we needed to review each case to be included in the analysis set for this manuscript to be confident that the scan had been ordered for a diagnostic indication. Based on our 200-case review, 53 Dx and 52 CUP cases were thought to be truly diagnosis cases, and the change in management frequencies observed in these cases were 20.8% (11 of 53) and 36.5% (19 of 52) for Dx and CUP, respectively. This was used to guide our sample-size estimate for an expanded review. To bind the half width of the 95% confidence interval to be 0.05, we determined that 308 Dx and 389 CUP confirmed cases were needed for the analysis. Given that we found approximately 50% of the cases to have been incorrectly categorized as diagnosis cases and another 5% to have incomplete or missing PET reports, we randomly selected 678 Dx and 856 CUP new cases for review, using only the first scan for any patient who had more than one PET scan for a diagnosis indication. The Dx and CUP reports were reviewed in a randomly assigned order by one author (R.S., a dual board-certified radiologist and nuclear medicine physician) to assess whether the PET report contained sufficient information to determine that the imaging reason recorded on the pre-PET form was correct. The cases were reviewed until at least 308 Dx and 389 CUP “confirmed” cases were found. The number of PNS cases in the database was deemed small enough that all could be reviewed. PNS reports were reviewed by a third-year nuclear medicine resident (A.S.). The review assessed whether the PET report contained sufficient information to determine that the reason for the study selected on the pre-PET form was correct; the cases meeting this criterion were used in the analysis. In addition, the PNS reviewer further categorized, if possible, the type of PNS suspected (i.e., endocrine, hematological, mucocutaneous, neurological, or other) and the suspected causal primary cancer.
Endpoints As used in prior NOPR reports, this study’s primary endpoint was the impact of PET on physicians’ intended management, dichotomized on both the pre- and post-PET forms as either treatment (e.g., surgery, chemotherapy, radiation or other
OTncologist he
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Subramaniam, Shields, Sachedina et al. treatment, alone or in combination) or nontreatment (i.e., watching, noninvasive imaging, biopsy, or supportive care). A change in management was defined as a switch after PET from treatment to nontreatment or vice versa. In addition, as we have previously reported [14], to address overestimation of the impact of PET by inclusion of cases where the pre-PET plan was imaging, we computed an “imaging-adjusted impact” by assuming no change in intended management for all cases where the initial management plan was alternative imaging. This estimate is likely to represent a worst-case lower boundary on the impact of PET on the intended management plan.
Statistical Analysis For the analyses, we first evaluated the difference between the selected cases for each indication in this study cohort and all NOPR patients with respect to demographic characteristics, including age, sex, ethnicity, race, Eastern Cooperative Oncology Group performance status, pre-PET summary stage, cancer type, scan type, and facility location.Then, we reported the impact of PET on physicians’ intended management and on the imaging-adjusted change in management. The proportions and the corresponding 95% confidence intervals calculated via the Exact method were reported. To compare the change in management across groups (i.e., Dx, CUP, and PNS), pairwise two-proportion t tests were performed to assess the significance of the difference. Bonferroni correction was applied to adjust for multiple comparisons. For the impact of PET on physicians’ intended management, we further broke down the assessment by different goals of treatment (i.e., nontreatment, curative treatment, palliative treatment). Last, we reported the post-PET actions, with the primary aim of determining whether PET can allow referring physicians to avoid ordering other tests.
RESULTS Review of Reports Based on our report review, we found that 326 of 650 (50.2%), 403 of 655 (61.5%), and 142 of 682 (20.8%) of Dx, CUP, and PNS studies, respectively, were initially correctly categorized. Accordingly, we estimate that approximately 10% of NOPR PET studies (supplemental online Appendix) were performed for these diagnostic indications during the 2006–2009 study interval. The substantially lower frequency of correctly categorized reports in the PNS group was attributable to incorrect classification (59.8%) or insufficient information in the PET reports for classification (20%).
Cohort Characteristics The age, sex, and ethnicity of the patients in our sample were similar to those in the overall NOPR cohort. The mean age was 73 years and approximately 15% of patients were younger than 65 or older than 85 years. Approximately 11% of the Dx and one-quarter of the CUP and PNS patients had performance status of 2 or greater. The scans in the cohort were PET/CT, rather than standalone PET, in 88.7%, 86.6%, and 92.2% for Dx, CUP, and PNS, respectively, and were performed at hospital-based facilities rather than freestanding clinics in 30.7%, 29.8%, and 18.1%, respectively.
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In 44% of cases, a suspected primary cancer type was not provided on the pre-PET form. In the remaining 56% of cases, the most common suspected cancer types in the Dx group, both in this cohort and in the full NOPR cohort, were cancer of the pancreas (22.7%), liver/intrahepatic bile ducts (16.0%), and kidney/urinary tract (12.3%). The dominant site of metastasis among CUP cases was liver (28.5%), bone/bone marrow (19.4%), isolated lymph nodes (17.1%), and lung (11.4%).
Change in Intended Management Table 1 summarizes changes in referring-physician management plans. Intended management was changed significantly more frequently in the CUP group (43.1%) than in the Dx (23.9%) and PNS (25.4%) groups (CUP vs. Dx, p , .0001; PNS vs. Dx, p , .0001; and CUP vs. PNS, p , .0002) (Table 2).The rates of change were not significantly different when comparing the Dx and PNS cohorts. The imaging-adjusted impacts were similar across all three indications (16.9%–19.5%); by comparison, the imaging-adjusted impact for all NOPR restaging cases during this time interval was 15.1% (95% confidence interval [CI], 14.7%–15.5%; n 5 30,911) [15].
Post-PET Intended Actions Referring physicians reported that, in light of PET results, they were able to avoid further testing in approximately three-fourths of patients (71.8%–74.6%) (Table 3). They also reported that a suspected site of the primary cancer was identified in 47.5% of CUP scans and 27.5% of PNS scans. At the time when the post-PET forms were completed, biopsies of suspicious sites had been performed in 21.2%, 32.4%, and 23.2%, respectively, of Dx, CUP, and PNS cases. The results of these biopsies are not known because these data were not collected by the NOPR.
DISCUSSION This study’s objective was to estimate the impact of FDG-PET on intended management, after correcting for misclassification, for three groups of cancer diagnosis indications in Medicare beneficiaries: initial cancer diagnosis, detection of unknown primary cancer, and paraneoplastic syndrome. We found that the frequency of change in intended management within these three groups was 24% for Dx, 25% for PNS, and 43% for CUP. These frequencies are in the range we previously reported for change in intended management when PET is used for initial staging, restaging, and detection of recurrence in patients with proven cancer (approximately 36%) [13]. In each subgroup, the referring physicians judged that PET allowed them to avoid further testing in approximately threequarters of patients, thereby potentially streamlining assessment and saving the costs of additional imaging or other testing. Although establishing a diagnosis of cancer depends on tissue sampling and cytologic or histologic assessment, FDGPET has been used to assess the likelihood of malignancy when a suspicious lesion is detected on other imaging studies. This application of PET has been most widely studied in the evaluation of solitary pulmonary nodules [17], which was one of the first two indications for FDG-PET covered by the Medicare program beginning in 1998. PET has been shown to ©AlphaMed Press 2016
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Table 1. Impact of positron emission tomography on intended management Parameter
Dx
CUP
PNS
No. of scans per indication Nontreatment to nontreatment, no. (%) Treatment to treatment, no, (%) Nontreatment to treatment, no, (%) Treatment to nontreatment, no. (%) Change in management, % 95% confidence interval, % Imaging-adjusted changea in management, % 95% confidence interval, %
326 226 (69.3) 22 (6.7) 51 (15.6) 27 (8.3) 23.9 19.3–28.6 18.4 14.2–22.6
403 141 (35.0) 88 (21.8) 140 (34.7) 34 (8.4) 43.2 38.3–48.0 18.9 15.0–22.7
142 91 (64.1) 15 (10.6) 22 (15.5) 14 (9.9) 25.4 18.2–32.5 16.9 10.7–23.1
a
Imaging-adjusted impact: No benefit from positron emission tomography (PET) was assumed for cases with a plan, before PET, of alternative imaging. Abbreviations: CUP, cancer of unknown primary origin; Dx, diagnosis of suspected cancer; PNS, paraneoplastic syndrome.
be helpful in cancer diagnosis, serving as a method of “metabolic biopsy” when biopsy of a suspicious lesion is medically contraindicated, when the lesion is inaccessible, or when a prior biopsy failed or yielded indeterminate results [3, 4, 18]. In a study of 40 patients with lung masses in whom biopsy was not possible or had failed, Pitman et al. found that PET had sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for the diagnosis of cancer of 96%, 81%, 88%, and 93%, respectively [18]. In these patients, PET contributed to improved management by avoiding biopsy in PET-negative patients because the negative predictive value of PET was sufficiently high. In addition, most lesions that were positive on PET were malignant or required specific management based on histological characterization. Hain et al. reported similar results in 63 patients who underwent FDG-PET following an unsuccessful biopsy of a lung lesion or when biopsy was considered too dangerous [4]. On visual analysis PET yielded 90% and 100% PPV and NPV, respectively. There is limited published literature on the use of PET for evaluating lesions, other than lung lesions, suspected to be cancer. Beggs et al., in a cohort of 50 patients with a variety of nonthoracic masses in whom biopsy was contravened or indeterminate, reported that FDG-PET had sensitivity, specificity, PPV, and NPVof 100%, 89%, 89%, and 100%, respectively, for the diagnosis of cancer [3]. PET has been used in several small studies to distinguish benign from malignant pancreatic masses. A meta-analysis of these data performed by Orlando et al. found that the overall area under the receiver operating characteristic curve was higher for PET than for CT; specifically, when CT was considered indeterminate, the sensitivity of PET for detection of cancer was 100% with a specificity of 68% [19]. Risum et al. performed a prospective study of PET/CT in 101 women with ovarian masses and a moderate risk of malignancy based on CA-125 level, ultrasound findings, and menopausal status [20]. Based on pathological proof of diagnosis obtained in 97 patients, the sensitivity of PET/CT was 100% and the specificity was 92.5%. Our data for a wide range of less common tumors indicate that PEToften leads to a change in intended management when used to evaluate patients with a lesion suspected to be malignant. Referring physicians reported that PET was helpful in identifying the potential primary sites in 47.5% of our patients with CUP.This detection frequency is similar to that reported in
Table 2. Pairwise comparisons of change in management among three groupsa p valueb Comparison groups
Unadjusted
Imaging-adjusted
Dx to CUP Dx to PNS CUP to PNS
Impact on Patient Management of [18F]-Fluorodeoxyglucose-Positron Emission Tomography (PET) Used for Cancer Diagnosis: Analysis of Data From the National Oncologic PET Registry RATHAN M. SUBRAMANIAM,a,b ANTHONY F. SHIELDS,c ARCHANA SACHEDINA,d LUCY HANNA,e FENGHAI DUAN,e BARRY A. SIEGEL,d,f BRUCE E. HILLNERg a Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; bUniversity of Texas Southwestern Medical Center, Dallas,Texas, USA; cKarmanos Cancer Institute, Wayne State University, Detroit, Michigan, USA; dDivision of Nuclear Medicine, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri, USA; eCenter for Statistical Sciences, Brown University, Providence, Rhode Island, USA; fSiteman Cancer Center,Washington University School of Medicine, St. Louis, Missouri, USA; gDepartment of Internal Medicine and the Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA
Disclosures of potential conflicts of interest may be found at the end of this article.
Key Words. Cancer diagnosis x Cancer of unknown primary origin x Paraneoplastic syndrome x National Oncologic PET Registry
ABSTRACT Introduction. Weassessedtheimpactof[18F]-fluorodeoxyglucose (FDG)-positron emission tomography (PET) on intended managementofpatientsintheNational OncologicPETRegistry(NOPR)for three different diagnostic indications: (a) determining whether a suspicious lesion is cancer (Dx), (b) detecting an unknown primary tumor site when there is confirmed or strongly suspected metastatic disease (cancer of unknown primary origin [CUP]), and (c) detecting a primary tumor site when there is a presumed paraneoplastic syndrome (PNS). Methods. We reviewed a sample of randomly selected reports of NOPR subjects who underwent PET for Dx and CUP and all reports for PNSto find subjects foranalysis. For these studies, we evaluated the impact of PET on referring physicians’ intended management, based on their management plans reported before and after PET.
Results. Intended management was changed more frequently in the CUP group (43.1%) than in the Dx (23.9%) and PNS (25.4%) groups (CUP vs. Dx, p , .0001; PNS vs. Dx, p , .0001; CUP vs. PNS, p , .0002). Referring physicians reported that, in light of PET results, they were able to avoid further testing in approximately three-fourths of patients (71.8%–74.6%). At the time when the post-PET forms were completed, biopsies of suspicious sites had been performed in 21.2%, 32.4%, and 23.2%, respectively, of Dx, CUP, and PNS cases. Conclusion. Our analysis of NOPR data shows that PET appears to have a substantial impact on intended management when used for three common diagnostic indications. The Oncologist 2016;21:1079–1084
Implications for Practice: [18F]-fluorodeoxyglucose-positron emission tomography appears to have a substantial impact on intended management when used for three targeted diagnostic indications: (a) determining whether a suspicious lesion is cancer, (b) detecting an unknown primary tumor site in a patient with confirmed or strongly suspected metastatic disease, and (c) detecting a primary tumor site in a patient with a presumed paraneoplastic syndrome.
INTRODUCTION Positron emission tomography (PET)/computed tomography (CT) and PET alone with [18F]-fluorodeoxyglucose (FDG) are useful in a variety of common situations among patients with cancer, including staging for planning of initial treatment, detecting residual tumor after therapy, and detecting recurrent disease. PET is also helpful for several cancer diagnosis indications. These include determining whether a suspicious lesion is likely to be malignant (e.g., evaluation of a solitary pulmonary nodule) [1, 2] and assessing lesions with
indeterminate biopsy results or that are inaccessible for biopsy (so-called metabolic biopsy) [3, 4]; identifying the site of an unknown primary cancer in a patient with proven or strongly suspected metastatic disease [5–8]; and detecting an occult primary cancer in a patient with a suspected paraneoplastic syndrome [9–11]. The National Oncologic PET Registry (NOPR) was developed, under the sponsorship of the World Molecular Imaging Society (formerly the Academy of Molecular Imaging), to meet
Correspondence: Rathan M. Subramaniam, M.D., Ph.D., Department of Radiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas,Texas 75390, USA.Telephone: 214-645-2762; E-Mail: [email protected] Received September 13, 2015; accepted for publication May 12, 2016; published Online First on July 8, 2016. ©AlphaMed Press 1083-7159/2016/$20.00/0 http://dx.doi.org/ 10.1634/theoncologist.2015-0364
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©AlphaMed Press 2016
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the requirements of the Centers for Medicare & Medicaid Services (CMS) for coverage with evidence development (CED) of FDG-PET in Medicare beneficiaries with noncovered cancer types or indications. NOPR’s primary objective was to measure the impact of PET on referring physicians’ intended patient management by collecting questionnaire data before the PET scan and again after the PET results were available [12]. NOPR opened to accrual in May 2006. We have previously reported NOPR findings on the impact of PET on intended patient management for various cancer types and imaging indications. Overall, PET was associated with a change in intended management in about one third of cases, with minimal clinically important differences by cancer type, testing indication, or time period [13–15]. The use of PET for cancer diagnosis was explored in our initial publication of NOPR results [13], with the finding of a change from a nontreatment plan to a treatment plan, or vice versa, in 31.1% of 5,516 scans (representing 19.4% of all scans in the initial NOPR cohort). However, that initial publication did not separately assess the impact of PET for the three major diagnostic applications described above. The current report represents a more detailed analysis of NOPR data regarding the use of PET for cancer diagnosis.
METHODS NOPR Design and Workflow NOPR is a prospective data registry that collects information from the PET facility, from the physician requesting the PET scan, and from the interpreting physician’s PETreport. Detailed descriptions of NOPR operations, human subject protection procedures, and results for the impact of PET on physicians’ intended management were previously reported [12–15]. Both patient and referring physician consent were required for the research use of their data. The research conducted using NOPR data is registered as NCT00868582 at ClinicalTrials.gov. The questions completed by the referring physician on the prePET form and on the post-PET forms specific to the diagnostic indications are shown in the supplemental online Appendix.
Eligibility for Inclusion in the Analysis Set Between May 2006 and April 2009, data were collected for 132,946 scans performed at approximately 1,693 facilities. Consent from patients and referring physicians for use of the data for research purposes was obtained for 116,927 scans (88%), and 21,931 (18.7%) of these were performed for one of the three previously noted diagnostic indications: determining whether a suspicious lesion is cancer (Dx; n 5 14,072); detecting an unknown primary tumor site when there is confirmed or strongly suspected metastatic disease (CUP; n 5 6,966); and detecting a primary tumor site when there is a presumed paraneoplastic syndrome (PNS; n 5 893). The types of cancers in the diagnostic indications cohort included all those for which use of FDG-PET for diagnosis was covered by CMS only if the patient was enrolled in the NOPR during the study interval. The excluded types, therefore, were suspected breast, non-small cell lung, head and neck and esophageal cancers, lymphoma, and melanoma. Accordingly, the eligible population consisted of scans ordered to evaluate
patients suspectedofhaving oneoftheless frequent, noncovered cancer types. During our initial evaluation of data for scans ordered for these diagnostic indications, we became concerned that the imaging indication selected on the pre-PET form was incorrect in many instances. It seemed likely that “diagnosis” was selected on the pre-PET form in many instances when PET was being obtained to evaluate a suspicious lesion in a patient with a known cancer. Accordingly, we undertook a quality control analysis of a random sample of 200 cases (100 Dx and 100 CUP) in which we compared the recorded indication and the referring physician’s estimate of the patient’s summary stage on the pre-PET form with the description or documentation of the patient’s history and findings in the actual PETreport. As expected, based on our previous review of information included in NOPR PET reports [16], many of the reports contained insufficient information to determine if the selected indication was correct. Other reports clearly showed that the selected indication was likely incorrect. We determined, therefore, that we needed to review each case to be included in the analysis set for this manuscript to be confident that the scan had been ordered for a diagnostic indication. Based on our 200-case review, 53 Dx and 52 CUP cases were thought to be truly diagnosis cases, and the change in management frequencies observed in these cases were 20.8% (11 of 53) and 36.5% (19 of 52) for Dx and CUP, respectively. This was used to guide our sample-size estimate for an expanded review. To bind the half width of the 95% confidence interval to be 0.05, we determined that 308 Dx and 389 CUP confirmed cases were needed for the analysis. Given that we found approximately 50% of the cases to have been incorrectly categorized as diagnosis cases and another 5% to have incomplete or missing PET reports, we randomly selected 678 Dx and 856 CUP new cases for review, using only the first scan for any patient who had more than one PET scan for a diagnosis indication. The Dx and CUP reports were reviewed in a randomly assigned order by one author (R.S., a dual board-certified radiologist and nuclear medicine physician) to assess whether the PET report contained sufficient information to determine that the imaging reason recorded on the pre-PET form was correct. The cases were reviewed until at least 308 Dx and 389 CUP “confirmed” cases were found. The number of PNS cases in the database was deemed small enough that all could be reviewed. PNS reports were reviewed by a third-year nuclear medicine resident (A.S.). The review assessed whether the PET report contained sufficient information to determine that the reason for the study selected on the pre-PET form was correct; the cases meeting this criterion were used in the analysis. In addition, the PNS reviewer further categorized, if possible, the type of PNS suspected (i.e., endocrine, hematological, mucocutaneous, neurological, or other) and the suspected causal primary cancer.
Endpoints As used in prior NOPR reports, this study’s primary endpoint was the impact of PET on physicians’ intended management, dichotomized on both the pre- and post-PET forms as either treatment (e.g., surgery, chemotherapy, radiation or other
OTncologist he
©AlphaMed Press 2016
®
Subramaniam, Shields, Sachedina et al. treatment, alone or in combination) or nontreatment (i.e., watching, noninvasive imaging, biopsy, or supportive care). A change in management was defined as a switch after PET from treatment to nontreatment or vice versa. In addition, as we have previously reported [14], to address overestimation of the impact of PET by inclusion of cases where the pre-PET plan was imaging, we computed an “imaging-adjusted impact” by assuming no change in intended management for all cases where the initial management plan was alternative imaging. This estimate is likely to represent a worst-case lower boundary on the impact of PET on the intended management plan.
Statistical Analysis For the analyses, we first evaluated the difference between the selected cases for each indication in this study cohort and all NOPR patients with respect to demographic characteristics, including age, sex, ethnicity, race, Eastern Cooperative Oncology Group performance status, pre-PET summary stage, cancer type, scan type, and facility location.Then, we reported the impact of PET on physicians’ intended management and on the imaging-adjusted change in management. The proportions and the corresponding 95% confidence intervals calculated via the Exact method were reported. To compare the change in management across groups (i.e., Dx, CUP, and PNS), pairwise two-proportion t tests were performed to assess the significance of the difference. Bonferroni correction was applied to adjust for multiple comparisons. For the impact of PET on physicians’ intended management, we further broke down the assessment by different goals of treatment (i.e., nontreatment, curative treatment, palliative treatment). Last, we reported the post-PET actions, with the primary aim of determining whether PET can allow referring physicians to avoid ordering other tests.
RESULTS Review of Reports Based on our report review, we found that 326 of 650 (50.2%), 403 of 655 (61.5%), and 142 of 682 (20.8%) of Dx, CUP, and PNS studies, respectively, were initially correctly categorized. Accordingly, we estimate that approximately 10% of NOPR PET studies (supplemental online Appendix) were performed for these diagnostic indications during the 2006–2009 study interval. The substantially lower frequency of correctly categorized reports in the PNS group was attributable to incorrect classification (59.8%) or insufficient information in the PET reports for classification (20%).
Cohort Characteristics The age, sex, and ethnicity of the patients in our sample were similar to those in the overall NOPR cohort. The mean age was 73 years and approximately 15% of patients were younger than 65 or older than 85 years. Approximately 11% of the Dx and one-quarter of the CUP and PNS patients had performance status of 2 or greater. The scans in the cohort were PET/CT, rather than standalone PET, in 88.7%, 86.6%, and 92.2% for Dx, CUP, and PNS, respectively, and were performed at hospital-based facilities rather than freestanding clinics in 30.7%, 29.8%, and 18.1%, respectively.
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In 44% of cases, a suspected primary cancer type was not provided on the pre-PET form. In the remaining 56% of cases, the most common suspected cancer types in the Dx group, both in this cohort and in the full NOPR cohort, were cancer of the pancreas (22.7%), liver/intrahepatic bile ducts (16.0%), and kidney/urinary tract (12.3%). The dominant site of metastasis among CUP cases was liver (28.5%), bone/bone marrow (19.4%), isolated lymph nodes (17.1%), and lung (11.4%).
Change in Intended Management Table 1 summarizes changes in referring-physician management plans. Intended management was changed significantly more frequently in the CUP group (43.1%) than in the Dx (23.9%) and PNS (25.4%) groups (CUP vs. Dx, p , .0001; PNS vs. Dx, p , .0001; and CUP vs. PNS, p , .0002) (Table 2).The rates of change were not significantly different when comparing the Dx and PNS cohorts. The imaging-adjusted impacts were similar across all three indications (16.9%–19.5%); by comparison, the imaging-adjusted impact for all NOPR restaging cases during this time interval was 15.1% (95% confidence interval [CI], 14.7%–15.5%; n 5 30,911) [15].
Post-PET Intended Actions Referring physicians reported that, in light of PET results, they were able to avoid further testing in approximately three-fourths of patients (71.8%–74.6%) (Table 3). They also reported that a suspected site of the primary cancer was identified in 47.5% of CUP scans and 27.5% of PNS scans. At the time when the post-PET forms were completed, biopsies of suspicious sites had been performed in 21.2%, 32.4%, and 23.2%, respectively, of Dx, CUP, and PNS cases. The results of these biopsies are not known because these data were not collected by the NOPR.
DISCUSSION This study’s objective was to estimate the impact of FDG-PET on intended management, after correcting for misclassification, for three groups of cancer diagnosis indications in Medicare beneficiaries: initial cancer diagnosis, detection of unknown primary cancer, and paraneoplastic syndrome. We found that the frequency of change in intended management within these three groups was 24% for Dx, 25% for PNS, and 43% for CUP. These frequencies are in the range we previously reported for change in intended management when PET is used for initial staging, restaging, and detection of recurrence in patients with proven cancer (approximately 36%) [13]. In each subgroup, the referring physicians judged that PET allowed them to avoid further testing in approximately threequarters of patients, thereby potentially streamlining assessment and saving the costs of additional imaging or other testing. Although establishing a diagnosis of cancer depends on tissue sampling and cytologic or histologic assessment, FDGPET has been used to assess the likelihood of malignancy when a suspicious lesion is detected on other imaging studies. This application of PET has been most widely studied in the evaluation of solitary pulmonary nodules [17], which was one of the first two indications for FDG-PET covered by the Medicare program beginning in 1998. PET has been shown to ©AlphaMed Press 2016
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Table 1. Impact of positron emission tomography on intended management Parameter
Dx
CUP
PNS
No. of scans per indication Nontreatment to nontreatment, no. (%) Treatment to treatment, no, (%) Nontreatment to treatment, no, (%) Treatment to nontreatment, no. (%) Change in management, % 95% confidence interval, % Imaging-adjusted changea in management, % 95% confidence interval, %
326 226 (69.3) 22 (6.7) 51 (15.6) 27 (8.3) 23.9 19.3–28.6 18.4 14.2–22.6
403 141 (35.0) 88 (21.8) 140 (34.7) 34 (8.4) 43.2 38.3–48.0 18.9 15.0–22.7
142 91 (64.1) 15 (10.6) 22 (15.5) 14 (9.9) 25.4 18.2–32.5 16.9 10.7–23.1
a
Imaging-adjusted impact: No benefit from positron emission tomography (PET) was assumed for cases with a plan, before PET, of alternative imaging. Abbreviations: CUP, cancer of unknown primary origin; Dx, diagnosis of suspected cancer; PNS, paraneoplastic syndrome.
be helpful in cancer diagnosis, serving as a method of “metabolic biopsy” when biopsy of a suspicious lesion is medically contraindicated, when the lesion is inaccessible, or when a prior biopsy failed or yielded indeterminate results [3, 4, 18]. In a study of 40 patients with lung masses in whom biopsy was not possible or had failed, Pitman et al. found that PET had sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for the diagnosis of cancer of 96%, 81%, 88%, and 93%, respectively [18]. In these patients, PET contributed to improved management by avoiding biopsy in PET-negative patients because the negative predictive value of PET was sufficiently high. In addition, most lesions that were positive on PET were malignant or required specific management based on histological characterization. Hain et al. reported similar results in 63 patients who underwent FDG-PET following an unsuccessful biopsy of a lung lesion or when biopsy was considered too dangerous [4]. On visual analysis PET yielded 90% and 100% PPV and NPV, respectively. There is limited published literature on the use of PET for evaluating lesions, other than lung lesions, suspected to be cancer. Beggs et al., in a cohort of 50 patients with a variety of nonthoracic masses in whom biopsy was contravened or indeterminate, reported that FDG-PET had sensitivity, specificity, PPV, and NPVof 100%, 89%, 89%, and 100%, respectively, for the diagnosis of cancer [3]. PET has been used in several small studies to distinguish benign from malignant pancreatic masses. A meta-analysis of these data performed by Orlando et al. found that the overall area under the receiver operating characteristic curve was higher for PET than for CT; specifically, when CT was considered indeterminate, the sensitivity of PET for detection of cancer was 100% with a specificity of 68% [19]. Risum et al. performed a prospective study of PET/CT in 101 women with ovarian masses and a moderate risk of malignancy based on CA-125 level, ultrasound findings, and menopausal status [20]. Based on pathological proof of diagnosis obtained in 97 patients, the sensitivity of PET/CT was 100% and the specificity was 92.5%. Our data for a wide range of less common tumors indicate that PEToften leads to a change in intended management when used to evaluate patients with a lesion suspected to be malignant. Referring physicians reported that PET was helpful in identifying the potential primary sites in 47.5% of our patients with CUP.This detection frequency is similar to that reported in
Table 2. Pairwise comparisons of change in management among three groupsa p valueb Comparison groups
Unadjusted
Imaging-adjusted
Dx to CUP Dx to PNS CUP to PNS
