1 Department of Nuclear Medicine, University Hospital Bonn, Bonn 2 Department of Nuclear Medicine, University Hospital Freiburg, Freiburg 3 Department of Diagnostic Radiology, University Hospital Freiburg, Freiburg 4 Department of Hematology & Oncology, University Hospital Freiburg, Freiburg, Germany
* Correspondence to: Dr M. J. Reinhardt, Department of Nuclear Medicine, University Hospital Bonn, Sigmund-Freud-Strasse 25, D-53105 Bonn, Germany. Tel: +49-228-287-5186; Fax: +49-228-287-1016; Email: michael.reinhardt{at}ukb.uni-bonn.de
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Abstract |
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Patients and methods: CT and FDG-PET were performed in 40 HD, 17 indolent NHL and 44 aggressive NHL patients (29 women, 72 men; aged 41±14 years) in a median of 2 months after therapy. Progression-free survival was evaluated using the KaplanMeier method. Independent prognostic factors were identified by means of Cox proportional hazards model.
Results: CT imaging results were progressive disease (PD) in five, stable disease (SD) in 57, and partial response (PR) or complete remission (CR) in 39 patients. FDG-PET suggested residual lymphoma in 24 patients. Three-year progression-free survival rates after exclusion of five PD patients were: 100% (PET negative; CT: PR or CR), 81% (PET negative; CT: SD), 21% (PET positive; CT: SD) and 0% (PET positive; CT: PR). FDG-PET (P<0.0001) and bulky disease (P <0.05) were identified as independent prognostic variables.
Conclusions: Among lymphoma patients with PR and SD on CT, FDG-PET discriminated those destined to progress into a low risk of 20% and a high risk for recurrence of
80%.
Key words: computed tomography, fluorodeoxyglucose, Hodgkin's disease, non-Hodgkin's lymphoma, positron emission tomography
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Introduction |
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The effectiveness of [18F]fluoro-deoxy-D-glucose positron emission tomography (FDG-PET) for monitoring response to treatment in lymphoma patients has been shown in several studies during recent years [6]. Whether the oncologist might find combined analysis of post-therapeutic CT and FDG-PET advantageous for prediction of relapse in lymphoma patients is still unclear.
The objective of this study was to assess the accuracy of combined interpretation of morphological and functional cross-sectional imaging for prediction of individual response to treatment in HD and NHL patients.
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Patients and methods |
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Histology of biopsies was classified according to the WHO classification [7] for 61 NHL (16 women, 45 men; aged 44.8±13.7 years), and for 40 patients with classic HD (13 women, 27 men; aged 36±12.9 years). In detail, these were 17 indolent B-cell lymphomas, i.e. 15 nodal lymphomas (12 follicle center and three mantle cell lymphoma) and two extranodal lymphomas (two marginal zone B-cell lymphoma of MALT type), a further 44 aggressive lymphomas, i.e. 34 diffuse large B-cell lymphomas and 10 T-cell lymphomas (five each of anaplastic large cell and peripheral T-cell lymphomas), and finally 23 nodular sclerosis, 13 of mixed cellularity, three lymphocyte-rich and one lymphocyte depletion HD. All patients were staged according to Ann Arbor clinical staging [8
]. Five patients had stage I, 36 patients had stage II, 27 patients had stage III and 33 patients had stage IV disease. A total of 56 patients presented with B-symptoms and 47 patients had bulky disease.
Chemotherapy of HD patients followed third (HD7-HD9) and fourth (HD10-HD12) generation study protocols of the German Hodgkin-Lymphoma Study Group (GHLSG) [9, 10
]. All but five NHL patients received chemotherapy with either CHOP (cyclophosphamide, vincristine, prednisone, doxorubicin) or VACOP-B (etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin) regimens. Radiotherapy was performed in 40 patients with HD and NHL a few weeks after the end of chemotherapy as extended-field (GHLSG protocols HD7 and HD8) or involved-field radiation.
An additional 26 patients (20 NHL, six HD), with partial response (PR) or stable disease (SD) on CT imaging and negative findings on FDG-PET imaging in 24 cases and positive PET findings in two cases, received subsequent salvage therapy without histological confirmation of imaging results and were therefore not considered for evaluation in this study. All patients provided oral or written informed consent after the nature of the imaging studies was fully explained.
Post-treatment evaluation and follow-up
Post-treatment FDG-PET and CT of the neck, thorax and abdomen were analyzed in routine clinical fashion. At the time of image evaluation, the interpreters were unaware of the results of the competitive study.
Median time interval between end of therapy and FDG-PET was 8 weeks (range 116) and median time interval between FDG-PET and CT scans was 10 days (range 144). Discrepant findings between CT and FDG-PET were verified by biopsy in nine cases and long-term follow-up including surveillance CT scans and other imaging methods as extracted from the patients medical files in all other cases. Median follow-up period in patients without relapse was 138 weeks or 32 months (142±53 weeks; range 55260). Definition of response to treatment followed the suggestions of the Cotswold meeting in HD [11] and of the National Cancer Institute International Working Group in NHL [12
].
CT imaging
CT scans of the neck, thorax and abdomen were performed using a fourth generation helical CT-system (Somatom +4; Siemens AG, Erlangen, Germany). Imaging parameters were 130 kV and 50 mAs for the neck, 130 kV and 40 mAs for the thorax, and 110 kV and 70 mAs for the abdomen. Eighty to 120 ml of intravenous contrast medium was administered using a power injector at a rate of 13 ml/s for all imaging studies. One liter of oral contrast was given in four portions for abdominal CT. Axial slices were reconstructed using standard methods. Reconstructed images had a thickness of 5 mm in the neck, 8 mm in the thorax, and 10 mm in the abdomen and pelvis. CT findings were described as complete remission (CR), unconfirmed complete remission (CRu), PR, SD and progressive disease (PD).
PET imaging
Patients fasted for 12 h before the PET study. Baseline glucose was limited below 130 mg/dl (7.2 mmol/l) before FDG injection. FDG-PET studies were performed 100±20 min after intravenous injection of 350450 MBq of 18F-FDG. Two-dimensional acquisitions were made using a dedicated PET system (Ecat Exact 921/31; Siemens AG) with a 10.8 cm transverse field of view. Seven to 10 bed positions were used to cover the area from the upper neck to the proximal femura. Three- to 8 min transmission and 9 min emission scans were obtained starting from the bladder immediately after urination to minimize bladder activity. Images were reconstructed iteratively by means of an ordered-subset expectation-maximization algorithm and segmented photon-absorption correction [13] and reoriented in transverse, coronal and sagittal planes. All foci of elevated 18F-FDG uptake were considered to represent viable lymphoma.
Statistics
The progression-free survival rates were estimated by the KaplanMeier method. Equivalence of survival curves was tested with the log-rank test. The Cox proportional hazards model was used to evaluate independent prognostic variables. Comparisons of groups for the probability of relapse and all other comparisons were performed with Fisher's exact test. P <0.05 was considered statistically significant. All analyses were carried out using SPSS for Windows 10.0.
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Results |
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Posttreatment evaluation with CT
Post-therapeutic CT indicated CR/CRu in 20 patients (19.8%), PR in 19 (18.8%), SD in 57 (56.4%) and PD in five patients (5%) in a median of 2 months after completion of therapy. Figure 1 shows the KaplanMeier progression-free survival estimates in dependence on CT imaging results. The 3-year progression-free survival rates were 100% for patients with CR, 79% for PR, 66.7% for SD and 0% for patients with PD. There was a significant difference in progression-free survival between PD and all other groups (P <0.00001), and between CR and PR (P <0.05) and SD (P <0.005), but not between SD and PR (P=0.281). When differentiating between HD, aggressive NHL and indolent NHL, the 3-year progression-free survival rates in CR patients were 100% for each histologic type, in PR patients the proportions were 90%, 62.5% and 100% for HD, aggressive NHL and indolent NHL, respectively; in SD patients they were 79.0%, 57.7% and 66.7%; and in PD every patient relapsed within 6 months (not shown).
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Post-treatment evaluation with FDG-PET
Post-therapeutic FDG-PET suggested residual lymphoma tissue in 24 patients (23.8%) in a median of 2 months after chemotherapy or chemo- and radiotherapy. The time interval between a positive PET and documented disease progress in patients not biopsied varied between 6 and 60 weeks (mean 23±17). Figure 2 shows the KaplanMeier progression-free survival estimates in dependence on FDG-PET results. The 3-year progression-free survival rates were 89.6% for patients with negative PET and 16.7% for patients with positive PET. This difference was significant (P <0.00001). When differentiating between HD, aggressive NHL and indolent NHL, the 3-year progression-free survival rates in PET negative patients were 94.1% for HD, 86.7% for aggressive NHL and 84.6% for indolent NHL, and in PET-positive patients were 33.3%, 7.1% and 25%, respectively (not shown).
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Discussion |
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However, appropriate timing might be even more useful when comparing the predictive value of FDG-PET obtained after the first cycle of chemotherapy [20] with that obtained after completion of therapy in our study. No disease progression for 1.5 years was predicted by a negative PET result in only 65% of patients when FDG-PET was performed after the first cycle of chemotherapy [20
]. This is significantly less than the 89.6% recurrence-free survival observed in our study when FDG-PET was performed after completion of treatment. Even though post-therapeutic FDG-PET was identified as the highest independent prognostic factor, a further improvement of diagnostic accuracy might be achieved by means of coregistered FDG-PET and CT [21
, 22
].
Several papers have addressed the prognostic value of post-therapeutic FDG-PET in HD and NHL patients [19, 23
29
]. Relapse rates within 2 years after therapy were 76% for PET-positive and 10% for PET-negative patients (P <0.001) in three studies with 168 patients, which did not distinguish between HD and NHL [23
25
]. A differentiation of 48 PET-negative lymphoma patients according to their CT imaging result yielded a higher progression-free survival at 2 years in PET- and CT-negative patients (87%) compared with those with negative PET but positive CT results (60%; P=0.055) [23
]. In five studies evaluating either HD or NHL patients [19
, 26
29
], overall relapse rates were 81.5% for PET-positive and 10% for PET-negative HD patients (137 cases) [19
, 26
, 27
], and 100% for PET-positive and 16.5% for PET-negative NHL patients (138 cases) [28
, 29
]. These results were largely comparable to those of the single modalities PET and CT in our study. The differentiation between HD, aggressive NHL and indolent NHL in our study revealed only minor differences concerning the predictive value of post-therapeutic FDG-PET. FDG-PET has been evaluated for primary staging of low-grade NHL in 42 patients [30
] and for detection of disease recurrence in 15 patients [31
]. These authors observed a significant contribution of FDG-PET to the management of follicular lymphoma but not of other subtypes. In particular, the detection of bone marrow involvement by FDG-PET was reported to be unacceptably low [30
, 31
]. A possible explanation might be the limited technical conditions of these studies concerning the lower spatial resolution of the PET scanner used and the lack of attenuation correction. Our data including 17 patients with indolent NHL indicated that FDG-PET might contribute to the treatment evaluation of indolent NHL patients when an adequate imaging technique is used.
A general weakness of this study is the lack of histologic proof in 52 of 61 cases (85%) with discrepant findings between PET and CT. Systematic biopsies of the various sites possibly involved by lymphoma could not be performed for ethical reasons. However, this limitation is inherent to all imaging studies in the field of lymphoma. Another limitation is that 25% of lymphoma patients with a negative PET scan who were probably cured of their disease received further treatment without histologic confirmation and therefore could not be included in the study. The resulting smaller number of patients and the heterogeneity of subtypes made some subgroup analyses difficult to interpret. Thus, confirmation of our data on a larger number of patients is warranted.
In conclusion, combined evaluation of CT and FDG-PET yielded a more differentiated assessment of individual prognosis of lymphoma patients than the single modalities. HD as well as aggressive and indolent NHL patients destined to progress among those with PR and SD on CT could be differentiated according to post-therapeutic FDG-PET into low risk for relapse of 20% and high risk for relapse of
80%. A posttherapeutic differentiation of prognostic groups to individualize therapy should therefore include FDG-PET for HD and NHL patients with PD and SD on CT imaging.
Received for publication January 28, 2005. Revision received April 4, 2005. Accepted for publication April 13, 2005.
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