Use of 18F-FDG PET/CT as an Initial Staging Procedure for Stage II–III Breast Cancer: A Multicenter Value Analysis

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  • 1 University of California, San Francisco, San Francisco, California;
  • | 2 University of Minnesota, Minneapolis, Minnesota;
  • | 3 Georgetown University, Washington, DC;
  • | 4 University of Alabama at Birmingham, Birmingham, Alabama; and
  • | 5 Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California.

Background: Metastatic staging imaging is not recommended for asymptomatic patients with stage I–II breast cancer. Greater distant metastatic disease risk may warrant baseline imaging in patients with stage II–III with high-risk biologic subtypes. NCCN Guidelines recommend considering CT of the chest, abdomen, and pelvis (CT CAP) and bone scan in appropriate patients. CT CAP and bone scan are considered standard of care (SoC), although PET/CT is a patient-centered alternative. Methods: Data were available for 799 high-risk patients with clinical stage II–III disease who initiated screening for the I-SPY2 trial at 4 institutions. A total of 564 complete records were reviewed to compare PET/CT versus SoC. Costs were determined from the payer perspective using the national 2018 Medicare Physician Fee Schedule and representative reimbursements to the University of California, San Francisco (UCSF). Incremental cost-effectiveness ratio (ICER) measured cost of using PET/CT per percent of patients who avoided a false-positive (FP). Results: The de novo metastatic disease rate was 4.6%. Imaging varied across the 4 institutions (P<.0001). The FP rate was higher using SoC versus PET/CT (22.1% vs 11.1%; P=.0009). Mean time between incidental finding on baseline imaging to FP determination was 10.8 days. Mean time from diagnosis to chemotherapy initiation was 44.3 days with SoC versus 37.5 days with PET/CT (P=.0001). Mean cost per patient was $1,132 (SoC) versus $1,477 (PET/CT) using the Medicare Physician Fee Schedule, with an ICER of $31. Using representative reimbursements to UCSF, mean cost per patient was $1,236 (SoC) versus $1,073 (PET/CT) for Medicare, and $3,083 (SoC) versus $1,656 (PET/CT) for a private payer, with ICERs of −$15 and −$130, respectively. Conclusions: Considerable variation exists in metastatic staging practices. PET/CT reduced FP risk by half and decreased workup of incidental findings, allowing for earlier treatment start. PET/CT may be cost-effective, and at one institution was shown to be cost-saving. Better alignment is needed between hospital pricing strategies and payer coverage policies to deliver high-value care.

Background

Breast cancer accounts for 30% of new cancer diagnoses in women, with approximately 276,480 new invasive breast cancers expected in the United States in 2020.1 The likelihood of metastatic disease at presentation is stage-dependent. Some studies have shown de novo metastatic disease rates of 15% in patients with stage II disease2 and >40% in patients with stage III disease.3,4 Greater metastatic disease risk in clinical stage II–III breast cancer may warrant baseline staging imaging, because treatment approaches for patients with distant metastatic disease are different for those with early-stage or locally advanced disease. Detection of distant metastases at diagnosis is also critical for identifying the correct patient population for clinical trials in adjuvant and neoadjuvant settings.5

18F-FDG PET/CT (PET/CT) is effective in detecting regional and distant metastases48 and has outperformed standard imaging techniques in the detection of bone, lymph node, and liver metastases.9,10 PET/CT has shown little value in staging of low-risk breast cancer,11,12 but may be appropriate for clinical stage II–III disease, because PET/CT requires only a single test and is more sensitive and specific than standard imaging.1317

Guidelines, including those of NCCN, suggest when PET/CT for clinical stage II or operable stage III breast cancer is not indicated and conversely when it may be helpful. PET/CT is recommended as a supplement to standard imaging studies, such as CT of the thorax and/or abdomen-pelvis and whole-body bone scans.18

The value of PET/CT for staging in non–small cell lung cancer is well established and considered cost-effective.1922 Similar analyses in breast cancer are less clear, especially in the United States.21,23 In silico analysis suggests that PET/CT is cost-effective for staging of clinical stage II–III breast cancer,24 but is not uniformly accepted.5 Lack of endorsement of PET/CT in guidelines and inadequate insurance coverage remain barriers to the use of PET/CT.

This study explored staging practices at 4 geographically different US cancer centers participating in the I-SPY2 trial, a neoadjuvant trial for patients with molecularly high-risk stage II–III breast cancer. We sought to determine the clinical value and cost-effectiveness of PET/CT as an initial staging procedure compared with standard imaging.

Methods

Study Design and Population

This study was approved by the University of California, San Francisco (UCSF) Institutional Review Board and Quantum Leap Healthcare Collaborative. I-SPY2 is a multicenter, prospective, randomized phase II trial that enrolls patients with clinical stage II–III invasive breast cancer, tumors ≥2.5 cm, and high-risk molecular features. I-SPY2 has been described previously in detail.25,26 Patients consenting to screening undergo baseline staging imaging to rule out metastatic disease before randomization using either PET/CT or CT of the chest, abdomen, and pelvis (CT CAP) and full-body bone scan (standard of care [SoC] imaging).

We retrospectively reviewed records of patients who consented to screening at 1 of 4 clinical sites—UCSF, University of Minnesota (UMinn), University of Alabama at Birmingham (UAB), and Georgetown University (GU)—from March 2010 through December 2017. Only participants whose records contained complete screening workup and follow-up assessments were included in the primary analysis.

False-Positive Rates

The primary outcome of interest was false-positive (FP) identification of metastatic disease, defined as incidental findings on PET/CT or SoC imaging that were investigated and proved benign via subsequent workup. Patients with FPs were defined as having at least one FP finding on baseline imaging. The determination of whether an incidental finding required workup to rule out metastatic disease was made by the treating clinician with guidance from the local institution’s radiologists as to how suspicious the lesion appeared. Examples of incidental findings included hypermetabolic bone lesions (possibly representing bone islands or Schmorl nodes), liver lesions (possible complex cysts, hemangiomas, or focal nodular hyperplasia), thyroid nodules, calcified and noncalcified “too small to characterize” pulmonary nodules, and enlarged and/or hypermetabolic lymph nodes (not including the axilla or internal mammary chains).

Time to initiation of neoadjuvant chemotherapy was the number of days between the date of core biopsy–proved cancer diagnosis and the date that neoadjuvant chemotherapy began. Time for determination of FP was the number of days between initial staging and completion of the corresponding workup.

Differences in de novo metastatic rates, procedures used between sites, and associations between patient characteristics and procedure type were evaluated by chi-square test. A z test was used to test for differences in FP rates between the PET/CT and standard imaging group. In addition, a Cochran-Mantel-Haenszel (CMH) test was used to compare the FP rates between imaging groups, controlling for site (or other clinical covariates) with the Breslow-Day test to assess the homogeneity of the association. Where significant heterogeneity in odds ratio was observed between classes, FP rates within each stratum were evaluated separately using the z test. For all other comparisons, a 2-tailed t test was applied. ANOVA was also used to compare time to treatment initiation between SoC and PET/CT groups, with site as a covariate.

Economic Evaluation

To evaluate the relative healthcare value of PET/CT, incremental cost-effectiveness ratio (ICER) was assessed, with health outcome defined as percent of patients who avoided an FP, calculated by subtracting 100 − %FP for SoC from 100 − %FP for PET/CT. The cost difference using PET/CT was determined by subtracting the mean cost of SoC imaging (baseline scan + FP workup costs) from the mean cost of PET/CT (baseline scan + FP workup costs). The ICER was calculated as cost difference using PET/CT divided by the percent of patients who avoided an FP using PET/CT.

An aggregate cost analysis of all 4 sites was performed by estimating costs of 18F-FDG PET/CT, SoC, and all workup procedures using the mean national 2018 Medicare Physician Fee Schedule (MPFS).27 Payments were derived through the Outpatient Prospective Payment System (OPPS). As section 5102(b) of the Deficit Reduction Act of 2005 obligates a payment cap on the technical component of certain diagnostic imaging procedures,28 the MPFS amount was compared with the OPPS payment amount. The lesser quantity, rounded to the nearest dollar, was used as the cost. HCPCS/CPT codes were used to derive outpatient and physician fees. No adjustments were made using the Consumer Price Index and no discounts were incorporated into calculating the costs. HCPCS/CPT codes used are shown in supplemental eTable 1 (available with this article at JNCCN.org).

Because UCSF has priced PET/CT lower than SoC within the past 3 years, a separate cost analysis of the UCSF cohort alone was also conducted. PET/CT, SoC, and workup procedure costs were estimated from reimbursements to the UCSF billing department. Representative reimbursement estimates for each procedure were calculated by averaging reimbursements for CPT codes of 20667 reimbursements from Medicare and 88185 reimbursements from a large commercial private payer from January 2017 through April 2018. Patients with FP workup that included CPT codes for which there was no reimbursement data available were excluded from this part of the analysis.

Results

Of the 812 patients consenting to screening from March 2010 through December 2017, 799 were assessed for de novo metastatic disease status (Figure 1). The de novo metastatic disease rate was 4.6% (37/799) and did not vary significantly across sites (P=.583) (Table 1).

Figure 1.
Figure 1.

CONSORT diagram for 812 patients screened for I-SPY2 from March 2010 through December 2017.

Abbreviations: GU, Georgetown University; SoC, standard of care; UAB, University of Alabama at Birmingham; UCSF, University of California, San Francisco; UMinn, University of Minnesota.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 18, 11; 10.6004/jnccn.2020.7598

Table 1.

Detection of De Novo Metastatic Disease by Cancer Center

Table 1.

Initial staging and subsequent workup of incidental findings, if applicable, were available for 564 patients (69.5%). Staging procedure varied between sites (P<.0001), with SoC imaging the principal technique used at UAB (92.8%) and GU (85.7%), and PET/CT most commonly used at UCSF (86.6%) and UMinn (63.6%). Chest radiograph was used for 29.5% of patients at UMinn. A small proportion of staging involved other techniques, such as bone scan with liver enzyme monitoring or CT CAP alone (Figure 2).

Figure 2.
Figure 2.

Variation in initial staging procedures among 4 comprehensive cancer center sites. The types of procedures used for initial staging of patients with clinical stage II–III breast cancer were significantly different when comparing 4 geographically diverse US comprehensive cancer centers (P<.0001).

Abbreviations: GU, Georgetown University; SoC, standard of care; UAB, University of Alabama at Birmingham; UCSF, University of California, San Francisco; UMinn, University of Minnesota.

aIncludes bone scan alone, CT of the chest, abdomen, and pelvis alone, and liver function test monitoring with or without imaging.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 18, 11; 10.6004/jnccn.2020.7598

Characteristics of the 529 patients who underwent SoC (n=231) or PET/CT (n=298) imaging and were included in the primary analysis are shown in Table 2. Mean age of both groups was 49 years (range, 25–81 years). A greater proportion of Asian women received PET/CT, whereas Black women tended to receive SoC (P<.0001). Tumor receptors and lymph node status or invasive cancer type were similar between the 2 groups, although there was a trend for hormone receptor (HR)–negative/HER2-negative patients to receive SoC rather than PET/CT (32% vs 23.5%).

Table 2.

Patient Demographics

Table 2.

Significantly more patients with FP results were identified in the group undergoing SoC (22.1%; 51/231) versus PET/CT imaging (11.1%; 33/298) (P=.0009). Within the SoC group, rates of FP were similar at UCSF, UAB, and GU (only 1 SoC imaging procedure was performed at UMinn), and rates of FP by PET/CT were similar across all sites (Table 3). FP rates for each imaging technique were similar across sites and the common odds ratio of FP stratified by site between the SoC and PET/CT groups was 2.4 (CMH P=.035).

Table 3.

Characteristics of Patients With FP Results

Table 3.

In contrast, significant heterogeneity in association was observed when patients were stratified by age group. A significant difference in FP rate between the SoC and PET/CT groups was observed among women aged <45 years (P=.0006), but not among those aged ≥45 years (P=.1302). No significant heterogeneity in associations were observed when patients were stratified by race or other tumor characteristics (Table 3).

Mean time from diagnosis to initiation of neoadjuvant chemotherapy was 44.3 days in the SoC group versus 37.5 days in the PET/CT group (P<.0001). As study sites also have significant differences in time to treatment initiation (1-way ANOVA P<.0001), we used 2-way ANOVA with imaging modality and study site as independent variables and observed significant main effects for both factors (site: P<.0001; imaging modality: P=.04). Mean time between incidental findings on staging imaging to determination of FP was 10.8 days. There was no significant difference in the time from initial staging procedure to determination of FP between the 2 groups (11.3 days for SoC vs 8.1 days for PET/CT) (Table 4).

Table 4.

Time From Diagnosis to Initiation of Neoadjuvant Chemotherapy and Initial Staging Procedure to Determination of FP

Table 4.

Table 5 lists costs of initial staging procedures and additional FP workup tests across sites. Mean cost per patient was $1,132 for SoC and $1,476 for PET/CT. Mean price increase over baseline imaging cost due to FP workup was 23.6% ($216) for SoC and 4.6% ($65) for PET/CT. Notably, 26 patients who underwent SoC (11.3%) were subsequently evaluated with PET/CT as part of their workup. The ICER was $31 for each percent of patients who avoided an FP.

Table 5.

Comparison of Total Costs by SoC Versus PET/CT Nationally and at UCSF

Table 5.

Using actual reimbursement estimates from Medicare at UCSF, mean cost per patient was $1,236 for SoC and $1,073 for PET/CT. The mean price increase over baseline imaging cost because of FP workup was 28.3% ($273) for SoC and 5.4% ($55) for PET/CT. In this cohort, the ICER was −$15 for each percent of patients who avoided an FP. When using estimates from a private payer, the mean cost per patient was $3,083 for SoC and $1,656 for PET/CT. The mean increase in price over baseline imaging cost because of FP workup was 15.1% ($404) for SoC and 8.7% ($132) for PET/CT. In this cohort, the ICER was −$130 for each percent of patients who avoided an FP (Table 5).

Discussion

PET/CT has become increasingly prevalent for cancer staging,20 offering shorter scan duration9 and better diagnostic accuracy4,68,13 compared with SoC, with similar radiation doses.29 Yet, the dearth of cost-effectiveness studies and lack of endorsement of PET/CT in guidelines have posed barriers to coverage. This is exacerbated by the practice of hospitals pricing PET/CT higher than SoC, reducing the incentive for payers to cover PET/CT despite previous studies showing that it may be more sensitive and specific in detecting metastatic disease. With the ever-increasing cost of healthcare, there is opportunity for improvement in patient outcomes and reduction of costs if diagnostic procedures are optimized.30,31

Given differences in imaging pricing and reimbursement patterns across the United States, we expected varied staging practices between institutions. Although practice variation has been shown previously in stage 0–II breast cancer,32 our study confirmed the variability of imaging used in the population with stage II–III disease. The difference in use of PET/CT versus SoC observed in Black and Asian patients was likely driven by the predominant use of one imaging modality over another at sites where one race is more prominently represented in the trial.

FPs were more commonly noted in patients aged <45 years. Whereas rates of FPs were higher with SoC than PET/CT in all biologic subsets, the ratios of FPs were highest in triple-negative and HER2+ disease (4.5 and 2.1, respectively). Because these subtypes are more common in younger women, biologic differences likely drive the higher FP rate in younger patients, and greater consideration for routine use of PET/CT may be warranted.

Although the focus of this investigation was on differences between PET/CT and SoC in terms of cost-effectiveness and FP, the importance of diagnosing de novo stage IV disease in patients with locally advanced disease, as it relates to tailoring appropriate treatment and providing more accurate prognostic estimates to patients, cannot be underestimated. The de novo metastatic disease rate of 4.6% underscores the importance of staging imaging, especially within the setting of a neoadjuvant chemotherapy trial. The rate in I-SPY2 is lower than previously reported rates of 15% to 40% in patients with stage II–III disease,24,68,13 which may be due to selection bias for patients deemed fit for an intensive clinical trial, those without clinical suspicion of metastases, and those who may have had imaging performed at an outside institution to rule out distant metastases before referral to the trial.

Reducing FPs is of great value to patients, because FPs cause significant anxiety.3335 Our study corroborated the superior specificity of PET/CT shown previously,5,13,36 with an FP incidence rate half that of SoC. We showed further that FPs were resolved after approximately 11 days. This wait time creates significant anxiety for patients, who must cope with the possibility of having distant metastatic disease. FPs also may contribute to delays in starting chemotherapy, which can be detrimental to patients at high risk of recurrence,37 such as those enrolled in I-SPY2. Patients who underwent PET/CT started chemotherapy 6.8 days sooner than those who underwent SoC, after controlling for study site. This likely was due, at least in part, to the relative reduction in FPs for patients who underwent PET/CT, leading to fewer follow-up studies or confirmatory biopsies required. Furthermore, SoC can require scheduling of up to 3 separate appointments, which may have contributed to delays in baseline imaging for some patients. Given the authorization process that is currently often required before scheduling PET/CT, patients undergoing PET/CT might start treatment even sooner if this imaging was endorsed by guidelines and uniformly covered by insurance. However, the impact of institutional difference on timing in our study should not be understated. Future studies with larger numbers comparing imaging type within a single institution may be helpful.

Our study also highlighted financial toxicity associated with FP workup. Using national Medicare estimates, FP workup after SoC resulted in a greater percentage increase over baseline imaging cost than did FP workup after PET/CT. In addition, 11.3% of patients who received SoC subsequently underwent PET/CT as part of FP workup. Although the mean cost per patient after taking into account FP workup costs was still greater for patients who received PET/CT imaging (using national Medicare averages), the ICER of $31 for each percent patient who avoided an FP likely supports PET/CT as cost-effective in this setting.

Hospitals can price imaging studies to make PET/CT more competitive with SoC. If the price of PET/CT were the same as SoC in our aggregate cost analysis using national Medicare averages, the ICER would be −$14 and result in cost savings. Were this pricing policy instated, insurers might be more likely to reimburse PET/CT. SoC has been shown in multiple settings to be less sensitive and specific, yet remains mandated by insurance coverage, resulting in more appointments, FPs, patient anxiety, and possible delays to treatment.

When PET/CT was originally introduced, it was priced higher than SoC, but for at least the past 3 years, PET/CT has been priced lower at UCSF. Investigators worked with hospital administrators to ensure that pricing policy would not prohibit the use of more the patient-centered PET/CT approach. When using real estimates from Medicare and a large commercial private payer at UCSF where these pricing changes have been instituted, there were cost savings of $15 and $130 for each percent of patients who avoided an FP, respectively.

Our study had limitations. First, we could not determine FP rates between PET/CT and SoC given the retrospective nature of this study and incomplete data from follow-up scans. A prospective, randomized study in which patients undergo both imaging tests at baseline might be informative. Second, the aggregate cost analysis was based on national Medicare averages, which may overestimate or underestimate costs given local and regional reimbursement differences. Third, patients were screened for an intensive clinical trial at academic centers, where patients and procedures are carefully coordinated and monitored, affecting the generalizability of our results. Fourth, 4 patients excluded from the Medicare cost analysis and 3 patients excluded from the private payer cost analysis at UCSF due to unavailable reimbursement data were all among the PET/CT group. Although this was likely negligible given the relatively lower FP workup cost compared with baseline imaging cost, this may have overestimated the savings of using PET/CT. Fifth, although resolution of FPs is mandated before patients are randomized in I-SPY2, review of imaging results and decisions to workup incidental findings were likely variable at different sites. Nonetheless, these data provided insight into real-time practice variation and its consequences.

Conclusions

Greater awareness is needed regarding the impact of staging on patients, variation in cost, and ability to set price at the institutional level to keep PET/CT competitive with SoC. These data support reassessment of guidelines so that patients with stage II–III breast cancer, especially those with molecularly high-risk disease, can access PET/CT for staging. We suggest that institutions set PET/CT prices to be equivalent to or lower than those of SoC to encourage the use of PET/CT. We also suggest that Medicare and private payer reimbursement policies be reevaluated with this consideration in mind.

Acknowledgments

We would like to acknowledge Kara Campbell and Reese Fawley for their contribution to this research.

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Submitted September 20, 2019; accepted for publication May 25, 2020.

Author contributions: Study concept and design: Hyland, Varghese, Hirst, Esserman, Melisko. Data acquisition: Hyland, Beckwith, Khoury, Varnado. Cost analysis: Hyland, Varghese. Statistical analysis: Yau. Manuscript preparation: Hyland, Flavell, Esserman, Melisko. Critical revision: Chien, Yee, Isaacs, Forero-Torres, Esserman, Melisko.

Disclosures: Dr. Isaacs has disclosed that she is a consultant for PUMA, Seattle Genetics, Sanofi, Novartis, and Genentech. The remaining authors have disclosed that they have not received any financial consideration from any person or organization to support the preparation, analysis, results, or discussion of this article.

Funding: This work was supported by funding from Quantum Leap Healthcare Collaborative.

Correspondence: Michelle E. Melisko, MD, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, 1825 4th Street, San Francisco, CA 94158. Email: michelle.melisko@ucsf.edu

Supplementary Materials

  • View in gallery

    CONSORT diagram for 812 patients screened for I-SPY2 from March 2010 through December 2017.

    Abbreviations: GU, Georgetown University; SoC, standard of care; UAB, University of Alabama at Birmingham; UCSF, University of California, San Francisco; UMinn, University of Minnesota.

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    Variation in initial staging procedures among 4 comprehensive cancer center sites. The types of procedures used for initial staging of patients with clinical stage II–III breast cancer were significantly different when comparing 4 geographically diverse US comprehensive cancer centers (P<.0001).

    Abbreviations: GU, Georgetown University; SoC, standard of care; UAB, University of Alabama at Birmingham; UCSF, University of California, San Francisco; UMinn, University of Minnesota.

    aIncludes bone scan alone, CT of the chest, abdomen, and pelvis alone, and liver function test monitoring with or without imaging.

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