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© 2001 American Society for Clinical Oncology Prognostic Value of Positron Emission Tomography (PET) With Fluorine-18 Fluorodeoxyglucose ([18F]FDG) After First-Line Chemotherapy in Non-Hodgkin’s Lymphoma: Is [18F]FDG-PET a Valid Alternative to Conventional Diagnostic Methods?From the Departments of Nuclear Medicine, Oncology, Hematology, and Pathology, University Hospital Gasthuisberg and Catholic University of Leuven, Leuven, Belgium. Address reprint requests to Luc Mortelmans, MD, PhD, Department of Nuclear Medicine, University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium; email luc.mortelmans{at}uz.kuleuven.ac.be
PURPOSE: A complete remission (CR) after first-line therapy is associated with longer progression-free survival (PFS). However, defining CR is not always easy because of the presence of residual masses. Metabolic imaging with fluorine-18 fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET) offers the ability to differentiate between viable and fibrotic inactive tissue. In this study, we evaluated the value of PET in detecting residual disease and, hence, predicting relapse after first-line treatment in patients with non-Hodgkin’s lymphoma (NHL). PATIENTS AND METHODS: Ninety-three patients with histologically proven NHL, who underwent a whole-body [18F]FDG-PET study after completion of first-line chemotherapy and who had follow-up of at least 1 year, were included. Persistence or absence of residual disease on PET was related to PFS using Kaplan-Meier survival analysis. RESULTS: Sixty-seven patients showed a normal PET scan after first-line chemotherapy; 56 of 67 remained in CR, with a median follow-up of 653 days. Nine of these patients with a residual mass considered as unconfirmed CR received additional radiotherapy. Only 11 of 67 patients relapsed (median PFS, 404 days). Persistent abnormal [18F]FDG uptake was seen in 26 patients, and all of them relapsed (median PFS, 73 days). Because standard restaging also suggested residual disease, 12 patients received immediate secondary treatment. In 14 of 26 patients, only PET predicted persistent disease. From these patients, relapse was proven either by biopsy (n = 8) or by progressive disease on computed tomography or magnetic resonance imaging (n = 6). CONCLUSION: Persistent abnormal [18F]FDG uptake after first-line chemotherapy in NHL is highly predictive for residual or recurrent disease. In relapsing patients, PFS was significantly shorter after a positive scan than after a negative scan.
NON-HODGKIN’S LYMPHOMAS (NHL) are a heterogeneous group of diseases that differ with regard to histopathology, clinical behavior, response to therapy, and clinical outcome. Response to therapy and clinical outcome has considerably improved with the use of doxorubicin-containing chemotherapy regimens.1 Obtaining a complete remission (CR) is the main objective of first-line chemotherapy because it is usually associated with a longer progression-free survival (PFS), compared with a partial remission, which is associated with a poorer clinical outcome.2 However, differentiation between tumor and fibrosis after first-line treatment is a difficult problem, especially when a large mass at diagnosis does not disappear completely despite disappearance of all clinical and biologic abnormalities after treatment. Conventional radiographic characteristics cannot differentiate between active tumor and fibrosis because 30% to 60% of the patients have a residual mass after completion of therapy,3 and only 18% of these patients with persisting computed tomography (CT) abnormalities but without other signs of active disease will relapse.4 Magnetic resonance imaging (MRI) did not prove to be more useful than CT imaging.5 The first metabolic imaging tool that was largely independent of morphologic criteria was gallium-67 single-photon emission computed tomography (67Ga-SPECT). Although routinely used for the evaluation of residual masses after chemotherapy, it is particularly efficacious for mediastinal sites but less for the evaluation of the abdomen. Sensitivity and specificity of 67Ga-SPECT has been diversely appreciated.6 Over the last years, a large number of reports have demonstrated the potential role of fluorine-18 fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET) in the staging and treatment monitoring of a variety of cancers7-11 including lymphomas. In this study, we evaluated if posttreatment evaluation of NHL based only on [18F]FDG-PET is a valid alternative to conventional diagnostic methods (CDM). Can [18F]FDG-PET identify those patients with insufficient response to treatment and, thus, poorer clinical outcome?
Patient Population Between June 1995 and September 1998, 93 consecutive patients with histologically proven NHL, treated at the Department of Hematology and Oncology, University Hospital Gasthuisberg (Leuven, Belgium) and who underwent a [18F]FDG-PET scan at restaging in addition to CDM after first-line treatment, were retrospectively analyzed. CDM consisted of a clinical examination, laboratory screening, chest x-ray, CT of thorax and abdomen, ultrasound, bone-marrow biopsy, and, if indicated, MRI.
Treatment
[18F]FDG-PET Imaging
End of Treatment Evaluation Posttreatment [18F]FDG-PET scans were interpreted by two clinical reviewers and without any knowledge of clinical or CT data. All scans were scored either as positive or negative. Negative was defined as having no evidence of disease. Positive was defined as any focal or diffuse area of increased activity in a location incompatible with normal anatomy and suspect for residual disease.
Statistical Analysis
Ninety-three patients (59 male and 34 female) with NHL who received an [18F]FDG-PET scan after first-line therapy were included. The median age was 47 years (range, 2 to 77 years). All patients were staged according to the Ann Arbor clinical stage, and histology of biopsies was classified according to the Revised European American Lymphoma classification.17 Patient characteristics are listed in Table 1.
Of the 93 scans performed after chemotherapy, 26 scans showed residual abnormal [18F]FDG uptake, and 67 scans were considered negative. According to these findings, patients were divided into two groups. The results of posttreatment [18F]FDG-PET and CDM are shown in Fig 1.
PET-Positive Cases After First-Line Therapy In the group of 26 positive scans, all patients relapsed. The median disease-free survival was 73 days (range, 10 to 838 days). Because CDM also suggested residual disease, 12 patients in this group received immediate additional therapy (mean PFS, 34 days; range, 10 to 159 days). In the remaining 14 patients, only [18F]FDG-PET was positive for residual disease. Because CDM indicated no evidence of disease, no salvage treatment was administered until relapse was proven in this group either by biopsy (n = 8) or by progressive disease on CT or MRI (n = 6) during follow-up (mean PFS, 140 days; range, 11 to 838 days). All of these relapses occurred in the involved site as seen on PET scan, and no false-positive scans were reported. Specifications with regard to histology, sex, age, and stage are listed in Table 1. Examples of two positive PET studies but with CR on CDM are shown in Fig 2 and Fig 3. PFS in this group was calculated by Kaplan-Meier survival analysis and is shown in Fig 4.
PET-Negative Cases After First-Line Therapy Of the 67 patients with a negative PET scan, 56 are still in CR after a median follow-up of 653 days (range, 351 to 1,550 days). Nine of these 56 patients received additional radiotherapy because of residual mass on CT considered as unconfirmed CR or because of initial bulky disease. The remaining 11 patients with a negative PET scan relapsed after a median follow-up of 404 days (range, 42 to 933 days). In 10 patients, CDM also showed no evidence of disease. Four of these patients (initially stage IV) progressed rapidly, three (two with diffuse large-cell lymphoma and one with follicle center lymphoma) with a positive bone marrow biopsy and one (mantle-cell lymphoma) with meningitis carcinomatosa. The other six patients, all with histologically aggressive lymphoma, relapsed in nodular sites previously involved. Only one patient had a residual inguinal mass on CT, considered as partial response. This patient with a follicle center lymphoma relapsed in the lumbar spine outside this residual mass after a PFS of 933 days. PFS was also calculated in this group by Kaplan-Meier survival analysis, and results are shown in Fig 4.
Statistical Analysis
Our study clearly indicates the important role of [18F]FDG-PET in the posttreatment evaluation of NHL. There were no false-positive results and only 11 false-negative results on 93 PET scans performed. In 10 cases with a false-negative PET scan, CDM had no additional value in predicting residual disease. In one case, a residual mass, seen on CT, was considered as partial response. The patient relapsed in the lumbar spine outside this residual mass after 933 days. Structural imaging modalities require perturbation or enlargement of anatomic structure to suggest tumor. The introduction of high-resolution CT and MRI improved the ability to identify these morphologic changes but could not reliably predict the clinical outcome after therapy. Changes in anatomic structures are slow and initially enlarged tumor sites may remain enlarged without tumor activity because of the development of fibrosis and/or tumor necrosis. Some reports confirmed that the risk of relapse was not greater at the site of persisting radiologic abnormalities than in other parts of the body.18 MRI provides clinically useful information, but the low sensitivity rate (45%) demonstrated that MRI was not the ideal tool for predicting clinical outcome.3 Gallium scintigraphy is independent of morphologic criteria but uses the metabolic characteristics of tissue to detect residual tumor activity. 67Ga-SPECT became the standard metabolic imaging technique for the posttreatment evaluation of patients with lymphomas. As gallium is excreted in the bowel after hepatic uptake, it is of little clinical use for the interpretation of abdominal involvement, and a pretreatment scan must always be performed to confirm a gallium-fixing tumor.19 Additional correlation with CT is necessary because a nonspecific fixation in young patients with regenerating thymus after chemotherapy and nonspecific hilar activity has been described, which could lead to false-positive conclusions.20 Several reports demonstrated the potential role of gallium scintigraphy21,22 to discriminate between residual tumor and fibrosis. Hence, the inherent superior resolution of PET imaging methods, the 1-day protocol, and the better interpretation of the abdomen are in favor of [18F]FDG-PET. [18F]FDG-PET, using increased glycolysis to differentiate between fibrosis and active tumor, was first reported by Paul23 as a functional imaging technique in lymphomas. During the last years, several reports have shown the effectiveness of [18F]FDG-PET in the posttreatment evaluation of lymphomas. De Wit et al24 and Zinzani et al25 reported a high predictive value of [18F]FDG-PET for the differentiation between active tumor versus fibrosis in patients with residual radiologic mass. In a study by Jerusalem et al,26 [18F]FDG-PET had a higher diagnostic and prognostic value in the posttreatment evaluation of lymphomas than CT scan (positive predictive value, 100% v 42%, respectively). The main disadvantage of these studies was the rather short follow-up and the small number of patients. In addition, there was no distinction made between patients with NHL and Hodgkin’s disease, two disease entities with clearly different histopathology, treatment, and prognosis. All these reports compared [18F]FDG-PET with CT scan as a diagnostic tool for detecting residual disease in patients with lymphoma. They concluded that [18F]FDG-PET is the most helpful noninvasive modality in differentiating tumor recurrence from fibrosis when CT scan showed a residual mass and that, if FDG-uptake is seen within the residual mass, strong consideration should be given to additional therapy. If FDG-uptake is seen outside of the residual mass, inflammatory lesions first have to be excluded. Posttreatment evaluation based only on [18F]FDG-PET, as an alternative to CDM, has never been tested in a large number of patients with NHL. In our study, 93 [18F]FDG-PET scans from patients with NHL were included and were evaluated without any clinical or radiologic information. Our data indicate that whole-body [18F]FDG-PET has a high prognostic value for posttreatment evaluation in NHL. All patients with a positive [18F]FDG-PET scan relapsed after a short PFS. No false-positive results were noticed. A negative scan on the contrary could not exclude minimal residual disease because 11 of the 67 patients with a negative PET scan relapsed. PFS was, however, significantly longer in this group (median PFS, 404 days) than in patients with a positive scan (median PFS, 73 days), and CDM had no additional value in predicting these relapses. This study definitely indicates that [18F]FDG-PET, by itself, is a valid alternative for posttreatment evaluation of NHL. Thus, based on our study, an [18F]FDG-PET scan after first-line therapy could be the standard procedure in routine clinical circumstances. If abnormal [18F]FDG-uptake is seen, further investigation is mandatory. This study showed that a negative [18F]FDG-PET scan does not exclude minimal residual disease and/or late relapse. In case of a negative [18F]FDG-PET result after chemotherapy, no further investigation at that time is necessary but these patients need close clinical follow-up, including a new [18F]FDG-PET scan, in case relapse is suspected. Further studies are necessary to determine the role of an early [18F]FDG-PET scan during chemotherapy to predict this late relapse and to analyze the reasons of a late relapse after a negative [18F]FDG-PET. Other studies will determine if the same results and conclusions are valid for Hodgkin’s disease.
Supported by grant no. G.0298.97 from the FWO-Vlaanderen. We thank Stefaan Vleugels for his technical support. P.V. and P.D. are postdoctoral researchers of the FWO-Vlaanderen.
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ABSTRACT
INTRODUCTION
Four patients with unconfirmed complete remission received additional radiotherapy.
