Cost Effectiveness of Positron Emission Tomography in Patients With Hodgkin's Lymphoma in Unconfirmed Complete Remission or Partial Remission After First-Line Therapy
To assess the cost effectiveness of fluorine-18–fluorodeoxyglucose positron emission tomography (FDG-PET) in patients with Hodgkin's lymphoma (HL) with unconfirmed complete remission (CRu) or partial remission (PR) after first-line treatment.
One hundred thirty patients with HL were prospectively studied. After treatment, all patients with CRu/PR were evaluated with FDG-PET. In addition, PET-negative patients were evaluated with standard follow-up, and PET-positive patients were evaluated with biopsies of the positive lesions. Local unit costs of procedures and tests were evaluated. Cost effectiveness was determined by evaluating projected annual economic impact of strategies without and with FDG-PET on HL management.
After treatment, CRu/PR was observed in 50 (40.0%) of the 127 patients; the sensitivity, specificity, and positive and negative predictive values of FDG-PET were 100%, 92.0%, 92.3%, and 100%, respectively (accuracy of 95.9%). Local restaging costs without PET were $350,050 compared with $283,262 with PET, a 19% decrease. The incremental cost-effectiveness ratio is −$3,268 to detect one true case. PET costs represented 1% of total costs of HL treatment. Simulated costs in the 974 patients registered in the 2008 Brazilian public health care database showed that the strategy including restaging PET would have a total program cost of $56,498,314, which is $516,942 less than without restaging PET, resulting in a 1% cost saving.
New technologic developments and growth in medical imaging are challenges for health care providers because they must balance patient care and health care costs. Positron emission tomography (PET) with fluorine-18–fluorodeoxyglucose (FDG) has been established as a tool for restaging Hodgkin's lymphomas (HL).1 Meta-analyses have shown PET to be more accurate than anatomic imaging (computed tomography [CT] and magnetic resonance imaging [MRI]) in differentiating viable tumor from benign fibrotic tissue in residual masses after therapy.2–9
Although the widespread use of PET restaging is a reality in some countries, it is not included as a tool for the evaluation of patients without complete remission in the Brazilian public health system. Clinical observation only for noncomplete responders may lead to disease progression and delay in second-line curative treatment. Early definition of disease activity may be feasible with the use of FDG-PET after treatment. The purpose of this prospective study, sponsored by the Health Ministry of Brazil, is to investigate the health care costs of including FDG-PET imaging in the evaluation of patients with HL with unconfirmed complete remission (CRu) or partial remission (PR) after first-line therapy.
Between August 2005 and December 2007, 130 consecutive patients presenting with newly diagnosed, biopsy-proven, classical HL from the Hematology Division of the São Paulo University Clinics Hospital were prospectively entered onto this study. Exclusion criteria included pregnancy and diabetes mellitus. The institutional and ethical review boards approved the study, and written informed consent was obtained from all patients. After diagnosis, patients were treated based on clinical staging (clinical and laboratory examinations, CT, bone marrow biopsy, and FDG-PET).
Stage I and II patients were treated with four to six cycles of chemotherapy using doxorubicin, bleomycin, vinblastine, and dacarbazine. Stage III patients were treated with six to eight cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine, and all stage IV patients were treated with eight cycles. Radiotherapy of involved fields was included in patients with clinical stage I and II submitted to four cycles of chemotherapy and when bulky disease (mass > 7 cm) was present, regardless of the clinical stage.
After first-line therapy, disease response was evaluated by CT and bone marrow biopsy (only for patients with previous bone marrow involvement). CT was interpreted by two board-certified radiologists, and analysis discrepancies were resolved by consensus. Bone marrow biopsy was evaluated by one expert hematopathologist and included immunohistochemical analysis. Complete remission (CR), CRu, PR, and relapsed/progressive disease were defined according to the International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphomas.10 Briefly, CR was defined as complete disappearance of all detectable clinical evidence of disease and disease-related symptoms, if present before therapy. CRu was defined as the presence of a residual mass greater than 1.5 cm in greatest transverse diameter that has regressed by more than 75% in the sum of the products of the greatest diameters. PR was defined as a more than 50% decrease in the sum of the products of the greatest diameters of the six largest dominant nodes or nodal masses.
All patients with CRu or PR after first-line treatment had a post-treatment FDG-PET scan; according to the protocol, patients with a positive test were evaluated with biopsy of the positive lesion, if feasible. Three patients died during first-line treatment and were excluded from the study. A biopsy could not be performed in one patient with PR, but the patient was considered as being positive because of the strong clinical evidence of disease. This patient was excluded from the accuracy analyses but not from the costs analysis.
All patients with CR and CRu/PR with a negative FDG-PET study were observed by means of physical examination and laboratory tests (every 2 months in the first year, every 3 months in the second year, every 4 months in the third year, every 6 months in the fourth year, and once a year thereafter). CT of neck, chest, abdomen, and pelvis with intravenous contrast was performed every 6 months in the first 3 years and then once a year until the end of the fifth year. All patients with biopsy-proven active HL, progression of disease on treatment, or no response and relapse underwent high-dose chemotherapy followed by autologous stem-cell transplantation (ASCT) according to local protocols.
All patients in CRu or PR underwent FDG-PET imaging for restaging at least 1 month after the completion of chemotherapy and 3 months after radiotherapy. The interval between the restaging CT and PET scans was 2 ± 12 days. These patients were not treated with second-line therapy before FDG-PET imaging.
Before FDG administration, the fasting glucose level was measured to document a blood glucose level less than 160 mg/dL. Whole-body PET imaging was performed after a 60-minute uptake period after the intravenous administration of 296 to 444 MBq (8 to 12 mCi) of FDG. Imaging was performed using two-dimensional acquisition in a GE Advance PET scanner (GE Health Care, Waukesha, WI). Attenuation maps for attenuation correction were obtained using germanium-68 sources.
Two experienced, board-certified, nuclear medicine physicians interpreted PET images independently with side-by-side CT correlation. The restaging FDG-PET was classified as positive or negative according to the consensus recommendations of the Imaging Subcommittee of International Harmonization Project in Lymphoma.1
The diagnostic accuracy of PET was measured using clinical follow-up in PET-negative patients and biopsy results in PET-positive patients, as reference standards. In PET-positive patients, the maximum standard uptake value (SUV) was compared with histopathology results. The SUVs of the biopsy-proven HLs were compared with false-positive lesions.
A decision tree with clinical standard pathway (Fig 1) was used to prospectively observe and quantify the health care tests and treatment resources required per stratum. Medications, procedures, and all other resources used local costs per unit. The Clinics Hospital is a state facility acquiring materials and medications through electronic or in-person statewide bids. The presented resources costs are annualized 2008 unit costs (rate of US$1.00 = R$1.00 [R$ represents real, the Brazilian currency]). Physician fees are not included.
Costs were averaged per group, annual economic impact of strategies with and without FDG-PET were projected on the public health care HL program, and cost effectiveness was estimated. Incremental cost-effectiveness ratio (ICER) was calculated by dividing the difference in costs of restaging with CT, PET, and biopsy versus with only CT and biopsy by the difference in positive predictive value between PET and CT.
SPSS 10.0 for Windows (SPSS, Chicago, IL) was used for the statistical analysis. Statistical significance was evaluated using the χ2 or t test. P < .05 was considered statistically significant; 95% CIs were used to assess parameter uncertainty.
Of the 130 patients included, 127 were restaged with the standard follow-up protocol (three patients were excluded as a result of death during treatment). Of these 127 patients, 74 (58.2%) were considered in CR, with a median follow-up time of 29 months (mean, 31.2 ± 9.6 months, with a total of 2,305.8 patient-months of observation); four of them developed recurrence of disease confirmed by biopsy. Three patients (2.4%) demonstrated progressive disease at the end of first-line treatment and were submitted to biopsy. All three patients had histologically confirmed HL and underwent high-dose chemotherapy followed by ASCT.
Fifty patients (39.4%) were considered to be in CRu/PR after first-line treatment and underwent restaging FDG-PET. An interpretation discrepancy occurred in one of the 50 patients and was resolved by consensus (Cohen's κ test, κ = 0.91). FDG-PET was negative in 23 patients (46%); the 1-year disease-free survival rate of these patients was 100%, with a follow-up time of at least 18 months (mean, 34 ± 12 months, with 666.5 patient-months of observation). FDG-PET was positive in 27 patients (54%); these patients were also observed for at least 18 months (mean, 26.5 ± 12 months, with 713.8 patient-months of observation). Twenty-four of 27 patients had confirmation of disease by a positive biopsy, and only one patient had confirmation of disease by clinical evidence of post-treatment progression; the average median time between restaging FDG-PET and biopsy was 48 ± 12 days. In the remaining two patients, histopathologic examination revealed inflammatory changes; one patient had pulmonary tuberculosis, and the other patient had a foam cell accumulation in the mediastinal lymph nodes. There was no evidence of recurrence of disease in these two patients during subsequent follow-up. Table 1 lists demographic and clinical data of the PET-positive and PET-negative groups.
|Characteristics||PET Negative ||PET Positive|
|No. of Patients||%||No. of Patients||%|
|Ann Arbor clinical stage|
Abbreviations: CRu, unconfirmed complete remission; PR, partial remission; PET, positron emission tomography.
The mean maximum SUV of the histopathologically proven malignant lesions was 6.4 (± 3.2), whereas the mean maximum SUV of the tissues with only inflammatory changes was 5.9 (± 3.1), resulting in a nonsignificant difference of 0.5 (t test, P = .21).
Sensitivity, specificity, and positive and negative predictive values of CT in HL restaging were 87.0%, 73.6%, 51.9%, and 94.5%, respectively. In this study, the sensitivity, specificity, and positive and negative predictive values of FDG-PET in patients with HL in CRu/PR were 100%, 92.0%, 92.3%, and 100%. Overall accuracy rates for CT and FDG-PET are 77.7% and 95.9%, respectively.
Treatment strategies with and without PET are shown in Figure 2. Costs of different restaging programs are listed in Table 2. Costs of the treatment of HL patients are listed in Table 3. Average costs were as follows: first-line therapy, $33,094; CT, $1,200; FDG-PET, $1,330; biopsy, $1,386; hospital admissions and procedures, $4,420; and salvage chemotherapy followed by ASCT, $50,800. For both strategies, the cost of patients with CR and patients with progressive HL is the same.
|Cost Center||Average Cost ($)||Costs of Restaging With PET ($) ||Costs of Restaging Without PET (n = 50; $)|
|PET Negative (n = 23)||PET Positive (n = 27)|
|Hospital and procedures||4,420||—||119,340||221,000|
Abbreviations: CRu, unconfirmed complete remission; PR, partial remission; PET, positron emission tomography; CT, computed tomography.
|Cost Center||Average Cost ($)||All Patients (N = 127) ||Cost of Restaging With PET ($) ||Cost of Restaging Without PET ($)|
|CR (n = 74)||Progression (n = 3)||CRu/PR|
|Cost ($)||% of Total Costs||PET Negative (n = 23)||PET Positive (n = 27)||CR (n = 74)||Progression (n = 3)||PR (n = 50)|
|Hospital and procedures||4,420||150,280||2.1||17,680||13,260||—||119,340||17,680||13,260||221,000|
|Standard follow-up and tests||7,987||1,014,349||14.0||591,038||23,961||183,701||215,649||591,038||23,961||399,350|
Abbreviations: CR, complete remission; CRu, unconfirmed complete remission; PR, partial remission; PET, positron emission tomography; CT, computed tomography.
Without PET in the restaging strategy, the 50 patients in CRu/PR would be submitted to surgical biopsy, summing $350,300. However, the use of PET in the 50 patients with CRu/PR would cost $66,500, and the additional biopsy in 27 PET-positive patients and hospital procedures would cost $156,735, implying a total cost of $283,262, which is a 19% cost savings in the restaging program with PET (Table 2).
The ICER comparing the restaging strategy of CT, PET, and biopsy with the restaging strategy of only CT and biopsy (without PET) would be −$3,268 [($5,665 − $7,005)/(0.92 − 0.51)] per true case detected. This means that compared with existing technology, it would cost $3,268 less to detect one true case using PET in the decision analysis.
The local program cost was $7,259,191 (Table 3) to treat and follow-up patients until the last visit, with an average cost of $57,160 per patient. Approximately two thirds of this estimate consists of unavoidable first-line treatment costs. In addition, the PET imaging costs represented 1% of the total program cumulative costs.
During 2008, the Brazilian public health care database recorded 974 patients with HL who were enrolled onto the Brazilian public health care system. If the empirical results of the study (58.2% of patients in CR, 39.4% of patients in CRu/PR, and 2.4% of patients with progressive disease after the first-line treatment) are projected to the health care system, there would be 567 patients with CR, 23 patients with progressive disease, and 384 patients with CRu/PR with suspicious masses. Table 4 shows the projection of costs to these 974 patients.
|Cost Center||Average Cost ($)||All Patients (N = 974) ||Cost of Restaging With PET ($) ||Cost of Restaging Without PET ($)|
|CR (n = 567)||Progression (n = 23)||PR|
|Cost ($)||% of Total Costs||PET Negative (n = 177)||PET Positive (n = 207)||CR (n = 567)||Progression (n = 23)||PR (n = 384)|
|Hospital and procedures||4,420||1,135,940||2.0||119,340||101,660||—||914,940||119,340||101,660||1,697,280|
|Standard follow-up and tests||7,987||7,779,338||13.8||4,528,629||183,701||1,413,699||1,653,309||4,528,629||183,701||3,067,008|
Abbreviations: CR, complete remission; CRu, unconfirmed complete remission; PR, partial remission; PET, positron emission tomography; CT, computed tomography.
First-line therapy would cost $32,233,556. The estimated 558 patients in CR observed according to the standard protocol would have an uneventful course valued at $4.5 million. Among the 384 patients in CRu/PR, 218 patients would be submitted to second-line therapy, summing approximately $11 million in addition to the $ 4.5 million of the standard follow-up tests. The total cost of the program would be $57,015,256 in these 974 patients.
If the strategy of treatment included PET in these 974 patients, first-line treatment would not change, including the standard tests for the estimated 567 patients in CR. However, the 384 patients in CRu/PR would be eligible to undergo PET imaging, adding $510,720 to the restaging protocol. Assuming the empirical probability observed of 46%, 177 PET-negative patients would undergo only standard follow-up, costing $1.5 million. The remaining 207 patients, with positive PET, would require biopsy. Projecting the 4% rate of patients with false-positive PET, approximately 192 patients with biopsy-proven HL would receive second-line therapy. Projecting costs estimated during the study for PET-positive patients, second-line therapy would cost almost $21 million. The strategy including the restaging PET would have a total cost of $56,498,314, showing a 1% cost saving ($516,942 less than the strategy without restaging PET).
Conventionally, response to treatment is assessed by measuring the change in tumor volume on CT, although reduction in size alone is not a reliable sign of treatment effectiveness.2,11 Approximately two thirds of patients have residual masses on CT after first treatment, and 40% are considered in CRu/PR (in our study, 60% patients presented with residual masses on CT, and 39.4% were considered in CRu/PR). However, CT cannot differentiate viable tumor from fibrosis in residual masses, and the positive predictive value of CT is poor.12–17
Our data show better results than the published literature regarding the effectiveness of restaging FDG-PET after first-line treatment for HL, with sensitivity, specificity, negative predictive value, and positive predictive value of 100%, 92%, 100%, and 92.5%, respectively. The meta-analysis by Zijlstra et al3 reported a pooled sensitivity and specificity for detection of residual disease in HL of 84% and 90%, respectively. PET has consistently demonstrated a high diagnostic accuracy, helping to exclude persistent disease.6,18 FDG-PET has also consistently been shown to have a high negative predictive value, which was greater than 90% in the current study and exceeds 80% in virtually all reported studies.19 However, these data are derived from all patients and not exclusively from patients judged to be in CRu/PR by CT criteria. In addition, the majority of published trials also included patients with aggressive non-Hodgkin's lymphomas. Thus, these data are not strictly comparable because patients with residual masses but in CR were not evaluated in our study. This previous selection with CT possibly allowed the reduction of potentially false-positive incidence in our results.
Our results show that 19% of the patients (24 of 123 patients) had histopathologically proven disease. Of the 26 PET-positive patients submitted to biopsy, only two patients had false-positive findings; 92.3% of patients had true-positive results. This is similar to the 3% prevalence of false-positive results reported by Castellucci et al20 in a study of 1,000 consecutive PET scans in patients with lymphoma. Because of the false-positive results, FDG-positive lesions need to be confirmed by biopsy.
The mean maximum SUV of the HL lesions with proven recurrence by histopathology was not significantly different from that of the false-positive lesions with only inflammatory changes. This confirms that maximum SUV cannot differentiate between HL and inflammation, which is in agreement with Dittman et al,21 who reported that SUV was not superior to visual assessment to detect the presence of residual disease.
Moreover, our prospective collection of costs demonstrates that FDG-PET imaging after first-line therapy for HL optimizes the use of health care resources. The impact of FDG-PET in the restaging program represents 1% of total costs of care for patients with HL. In addition, the costs of a program using restaging FDG-PET were 1% lower than a program without PET.
There are few studies regarding PET in Brazil.22,23 To our knowledge, this is the first prospective report of local hospital costs for management of patients with HL in a developing country. Other approaches to cost effectiveness have been performed by European groups using different patient populations. A study in France reported costs similar to those in this study; the mean unit cost of PET was approximately €800 per patient.24 Other groups have reported models with simulated costs, for example, the Scottish Health Technology Assessment Program.25 The Scottish model predicted that with CT, 36% of patients would receive unnecessary consolidation radiotherapy, increasing costs. If CT node-positive patients were also imaged by PET, only 6% of patients would receive consolidation therapy; and if CT was not used at all, only 4% of patients would receive unnecessary radiotherapy. This model showed that PET without CT or in CT node-positive patients was highly cost effective. Probabilistic sensitivity analysis showed that across a range of input values, the willingness to pay needed only to be £5,000 per life-year (as shown by the 95% or 99% point on the cost-effectiveness acceptability curves for three age sectors and each sex). Similar conclusions were reached by a Greek group reproducing the Scottish model.26 Both models also recommend that optimal stratification of post-therapy response should include FDG-PET. Biopsies do have morbidity, and the clinical impact of PET results that would prevent patients from undergoing unnecessary surgical procedures must be considered. The use of PET in the CRu/PR setting does not involve higher costs in the public health system economy. In contrast, PET would reduce costs to the public health system, with an ICER of −$3,268 to detect one true case. Usually, the ICER is considered acceptable if the cost is less than $50,000 to $100,000 per life saved.27
PET-CT scanners may optimize interpretation of both imaging modalities and allow more accurate localization of foci with increased FDG uptake than PET alone. However, our results are similar to some reports with PET-CT.28 This may be because PET and CT were carefully correlated side by side in this study.
The major drawback of all studies that analyze FDG-PET in HL is the small sample size. Our study also reflects the rather low incidence of this disease and its well-defined patient population. Furthermore, the 30-month average follow-up time was short; it is well known that HL can relapse after longer disease-free intervals. However, this is a preliminary report of an ongoing longitudinal study. Another limitation is the lack of histopathologic data in patients with negative FDG-PET findings but persistent residual masses because of ethical reasons.
The results of our study indicate that FDG-PET has a high negative predictive value. PET has been able to confirm all patients with absence of HL after first-line therapy. However, FDG-avid lesions need biopsy confirmation because false-positive results may occur in 4% of patients, usually as a result of comorbid inflammatory/infectious diseases. Optimal stratification of post-therapy response should include FDG-PET combined with pathology assessment. For patients with HL presenting in CRu/PR with suspicious residual masses after first-line therapy, restaging FDG-PET is highly cost effective, providing 19% cost savings to the local restaging program and 1% cost savings to the total public HL health care program.
Supported by the Brazilian Health Ministry.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Employment or Leadership Position: Dominique Delbeke, Society of Nuclear Medicine (U) Consultant or Advisory Role: Dominique Delbeke, GE Health Care (U) Stock Ownership: None Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: None
Conception and design: Juliano J. Cerci, Evelinda Trindade, Luís F. Pracchia, Valeria Buccheri, José C. Meneghetti
Provision of study materials or patients: Luís F. Pracchia, Felipe A. Pitella, Camila C.G. Linardi, José Soares Jr, Valeria Buccheri
Collection and assembly of data: Juliano J. Cerci, Evelinda Trindade, Luís F. Pracchia, Felipe A. Pitella, Camila C.G. Linardi, Valeria Buccheri
Data analysis and interpretation: Juliano J. Cerci, Evelinda Trindade, Luís F. Pracchia, Felipe A. Pitella, Camila C.G. Linardi, José Soares Jr, Valeria Buccheri
Manuscript writing: Juliano J. Cerci, Evelinda Trindade, Luís F. Pracchia, Camila C.G. Linardi, Dominique Delbeke, Leigh-Ann Topfer, Valeria Buccheri
Final approval of manuscript: Juliano J. Cerci, Evelinda Trindade, Luís F. Pracchia, Camila C.G. Linardi, Leigh-Ann Topfer, Valeria Buccheri, José C. Meneghetti
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