Departments of 1 Nuclear Medicine, 2 Hematology, 3 Oncology, 4 Microbiology and 5 Pathology, University Hospital Gasthuisberg and Catholic University of Leuven, Leuven, Belgium
Received 24 January 2002; revised 12 March 2002; accepted 27 March 2002
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Abstract |
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Less than half of all patients with aggressive non-Hodgkins lymphoma (NHL) are cured with standard chemotherapy. Therefore, it is important to distinguish between responders to standard treatment and non-responders who may benefit from an early change to a more effective therapy. This study was intended to assess the value of a midtreatment fluorine-18 fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) scan to predict clinical outcome in patients with aggressive NHL.
Patients and methods:
Seventy newly diagnosed patients with aggressive NHL, who were treated with doxorubicin-containing chemotherapy, underwent a [18F]FDG-PET scan at midtreatment. Presence or absence of abnormal [18F]FDG uptake was related to progression-free survival (PFS) and overall survival (OS) using KaplanMeier survival analysis. Multivariate analysis was performed to evaluate the effect of the International Prognostic Index (IPI) and early [18F]FDG-PET findings on PFS and OS.
Results:
At midtreatment, 33 patients showed persistent abnormal [18F]FDG uptake and none of these patients achieved a durable complete remission (CR), whereas 37 patients showed a negative scan; 31/37 remained in CR, with a median follow-up of 1107 days. Only 6/37 patients either achieved a partial response or relapsed. Comparison between groups indicated a statistically significant association between [18F]FDG-PET findings and PFS (P <1 x 105) and OS (P <1 x 105). In multivariate analysis, [18F]FDG-PET at midtreatment was a stronger prognostic factor for PFS (P <1 x 107) and OS (P <9 x 106) than the IPI (P <0.11 and P <0.03, respectively).
Conclusions:
Early restaging [18F]FDG-PET may be used to tailor induction chemotherapy in patients with aggressive NHL.
Key words: [18F]FDG-PET, non-Hodgkins lymphoma, therapy monitoring
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Introduction |
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Fluorine-18 fluorodeoxyglucose positron emission tomography ([18F]FDG-PET), using increased glycolysis to differentiate between fibrosis and active tumor, was first reported by Paul [7] as a functional imaging technique for the detection of lymphomas. There is now considerable evidence that [18F]FDG-PET after first-line chemotherapy is very useful in assessing the significance of residual masses and identifies those patients with insufficient response to treatment and hence poorer clinical outcome [8].
In this study, we assessed the value of a midtreatment [18F]FDG-PET scan to predict clinical outcome in patients with aggressive NHL, treated with doxorubicin-containing chemotherapy. If patients with a positive midtreatment scan never achieve a durable response to induction chemotherapy, a change from standard induction chemotherapy to new experimental approaches may be more effective.
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Patients and methods |
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Treatment
Patients were treated according to departmental protocols. Most patients (56/70) were treated at the Department of Hematology that participated in the DutchBelgian Hemato-Oncology Cooperative study HOVON 26: Intensified CHOP of 12-weeks duration [cyclophosphamide 1000 mg/m2 i.v. day 1, doxorubicin 70 mg/m2 i.v. day 1, vincristine 2 mg i.v. day 1, prednisone 100 mg x 5 p.o. days 15 and granulocyte colony-stimulating factor (G-CSF) 300 µg s.c. days 212; six courses] plus G-CSF as compared with standard CHOP (cyclophosphamide 750 mg/m2 i.v. day 1, doxorubicin 50 mg/m2 i.v. day 1, vincristine 2 mg i.v. day 1 and prednisone 100 mg x 5 p.o. days 15; eight courses) of 24-weeks duration (B. Löwenberg, Chairman, HOVON). Ten patients were treated at the Department of Oncology and received eight courses (3 weeks duration) of CHVmP/BV [9] (cyclophosphamide 600 mg/m2 i.v. day 1, doxorubicin 50 mg/m2 i.v. day 1, teniposide 60 mg/m2 i.v. day 1, prednisone 40 mg/m2 x 5 p.o. days 15; bleomycin 10 mg and vincristine at 1.4 mg/m2 i.v. day 15). Four pediatric patients received eight cycles of the United Kingdom Children Cancer Study Group (UKCCSG) 9002 protocol [10], a six-drug program including cyclophosphamide, vincristine, prednisolone, doxorubicin and methotrexate.
FDG-PET imaging
Whole-body [18F]FDG-PET scans were performed with a CTI Siemens ECAT 931 tomograph (SiemensCTI, Knoxville, TN, USA). All patients fasted for at least 6 h before [18F]FDG-PET scanning and the serum glucose level was measured before scanning. All patients had a glucose level <120 mg/dl and there were no diabetic patients. A dose of 370555 MBq [18F]FDG was administered intravenously as a bolus. Patients received a diuretic to minimize image artifacts due to urinary stasis and were kept well hydrated. Between injection and scanning, patients were asked to lie still to avoid muscular [18F]FDG uptake. A whole-body acquisition was performed 60 min after injection and consisted of 10 non-overlapping bed positions (4 min/bed-position) so that the total effective field of view extended from the upper part of the thighs to the head. The images were iteratively reconstructed [11].
Baseline evaluation
Before initiation of therapy, all patients were staged using conventional diagnostic methods (CDM), consisting of a clinical examination, laboratory screening, chest X-ray, CT scan of thorax and abdomen, ultrasound scan, bone-marrow biopsy and, if indicated, magnetic resonance imaging (MRI). Almost all patients (68/70) also received a pretreatment [18F]FDG-PET scan for staging and to confirm the [18F]FDG avidity.
Early treatment evaluation
All patients underwent a [18F]FDG-PET scan at midtreatment. Thirty-six patients received a [18F]FDG-PET scan after three cycles of polychemotherapy and 34 patients after four cycles. The interval [18F]FDG-PET scans were planned the day before the start of the next course of chemotherapy with a minimal interval of 2 weeks. [18F]FDG-PET images were interpreted by two expert readers in consensus with knowledge of initial clinical and CT data, but without other clinical information during treatment. 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 and/or new localizations.
Assessment of response after first-line treatment
One to 3 months after the end of the last course of chemotherapy, patients were re-evaluated by CDM. The results of conventional diagnostic tests and follow-up were drawn from the patients records. After restaging, patients remission status was assessed using recently reported standardized guidelines [12].
Statistical analysis
The aim of this study was to evaluate the role of early restaging [18F]FDG-PET in predicting progression-free survival (PFS) and overall survival (OS). Progression-free survival was defined as the time interval from the end of therapy to the first objective evidence of relapse/progression or end point of our study. Overall survival was calculated from the end of therapy until death. Survival curves were calculated by KaplanMeier survival analysis [13] and comparison between groups was performed by the log-rank test [14]. Multivariate analysis by proportional hazard (Cox) regression [15] was performed to evaluate the effect of the prognostic significance of IPI and early [18F]FDG-PET findings on PFS and OS.
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Results |
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Results of midtreatment [18F]FDG-PET in relation to clinical outcome
Of the 70 [18F]FDG-PET scans performed on these patients early during chemotherapy, 33 showed persistent abnormal uptake and 37 were considered negative. According to these findings, patients were subdivided into two groups. The results of midtreatment [18F]FDG-PET in relation to clinical outcome are shown in Figure 1.
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Discussion |
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Non-Hodgkins lymphoma comprises a heterogeneous group of lymphoma entities, which differ with regard to response to therapy and hence clinical outcome. In the past, the IPI was developed for predicting primary outcome in patients with aggressive NHL based on the patients clinical characteristics before treatment. The clinical features incorporated in the IPI reflect the biological heterogeneity of aggressive NHL. However, the duration of CR and thus long-term clinical outcome might be significantly more affected by the sensitivity of the tumor to the chemotherapy than the clinical prognostic factors. Until now, morphological imaging modalities (CT and MRI) using sequential determination of tumor size are performed to assess tumor response induced by chemotherapy. However, changes in anatomical structures can be slow and initially enlarged tumor sites may remain enlarged without tumor activity, due to the development of fibrosis and/or tumor necrosis. Morphological imaging modalities, as a criterion for early response monitoring, are inefficient for the differentiation between responders and non-responders [17, 18]. Several courses of chemotherapy are necessary before treatment effectiveness can be reliably determined. Using CT findings as a criterion for early response may label an unacceptable number of patients as poor responders and expose them to more aggressive or experimental therapy, even if these patients can achieve a durable complete response with the installed chemotherapy.
Gallium (67Ga) scintigraphy, using the metabolic characteristics of tissue to detect residual tumor activity, has been shown to be very useful in the monitoring of disease response. In a study by Kaplan et al. [19], 67Ga imaging proved to be an excellent indicator of residual viable tumor early during chemotherapy in 37 patients with diffuse large B-cell lymphoma. In a later study by Front et al. [20], the DFS was compared between patients (n = 118) with positive or negative 67Ga and CT scans. Computed tomography findings were not predictive of outcome in contrast to 67Ga imaging. Gallium scintigraphy was a good indicator of patients who may benefit from a change to a more aggressive treatment.
Despite the important role of 67Ga scintigraphy in the therapy monitoring of patients with NHL, [18F]FDG-PET seems to be the favorable technique because of the inherent superior resolution and sensitivity of PET imaging methods together with a better interpretation of the abdomen.
Recently, several reports [2123] concluded that [18F]FDG-PET is the most helpful non-invasive modality in differentiating tumors from fibrosis when a CT scan has shown a residual mass after completion of therapy in patients with lymphoma. Since more aggressive but also more toxic treatment modalities are available, and since the finding that patients with a rapid response to induction chemotherapy are likely to have a more durable CR, there is a growing interest in the role of [18F]FDG-PET for the therapy monitoring of aggressive NHL. Previous studies [24, 25] have shown that the decrease in [18F]FDG uptake in NHL during chemotherapy does reflect treatment-induced metabolic changes rather than partial volume effects or therapy-induced changes in blood glucose levels. Römer et al. [26] documented the extent and time course of changes in [18F]FDG metabolism in response to chemotherapy in 11 patients. Standard induction chemotherapy in NHL causes a rapid decrease of [18F]FDG uptake as early as 7 days after treatment. However, [18F]FDG uptake at 42 days correlated better with outcome than the 7 day parameters. Jerusalem et al. [27] presented a study of 28 patients who received a [18F]FDG-PET scan after a median of three cycles of polychemotherapy. Persistent abnormal uptake after a few cycles of chemotherapy was predictive of PFS and OS. The main disadvantage of this study was the rather small number of patients and, more importantly, the heterogeneity of the population. They included not only patients with newly diagnosed aggressive NHL, but also patients with a low grade or relapsing NHL.
Early treatment evaluation based on [18F]FDG-PET has never been tested in a large number of patients with aggressive NHL. We analyzed 70 newly diagnosed aggressive NHL patients who all received a [18F]FDG-PET scan early during doxorubicin-containing first-line chemotherapy. Our data indicate that persistent [18F]FDG uptake at midtreatment is predictive of PFS and OS. All patients with a positive midtreatment scan either relapsed rapidly after a transient CR, never achieved a CR or progressed during therapy. On the contrary, almost all patients with a negative midtreatment scan achieved a durable CR. A few patients with a negative midtreatment scan may still develop tumor progression. Interestingly, PFS in this group was longer (median PFS, 301 days) than in patients with a positive scan (median PFS, 45 days). Neither the [18F]FDG-PET scan nor the CT scan after completion of therapy could predict relapse in these patients.
Finally, and most importantly, our results indicate that [18F]FDG-PET at midtreatment is a stronger prognostic factor for PFS and OS than IPI. The IPI was developed to predict outcome in patients with aggressive NHL on the basis of the patients clinical characteristics before the start of treatment. It appears that when intensive regimens are used, the IPI is an important clinical prognostic factor predicting the chance of achieving a CR. However, the duration of the CR might be more significantly affected by the chemosensitivity of the tumor. Persistent abnormal [18F]FDG uptake after three to four cycles of chemotherapy might represent deposits of chemoresistant cell clones. Measuring rapid complete response to therapy by an early [18F]FDG-PET scan could further prognosticate outcome during treatment, eventually leading to an early change of therapy, which might improve survival. Since patients with an indolent lymphoma have different treatment options and outcome, and since the FDG avidity is variable, these findings cannot be extrapolated to indolent lymphoma.
In conclusion, this current prospective study suggests that early restaging [18F]FDG-PET is an important prognostic factor to outcome and may be used to tailor induction chemotherapy in patients with aggressive NHL. If [18F]FDG-PET findings remain positive at midtreatment, these poor prognosis patients may benefit from an early change in therapeutic approach. A prospective two-arm study is now warranted to compare clinical outcome in patients with positive midtreatment [18F]FDG-PET findings, who will continue to receive the installed induction therapy, and clinical outcome in patients with positive findings, where treatment will be changed to a more aggressive or more experimental one.
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Acknowledgements |
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Footnotes |
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