Departments of 1 Medicine and 4 Radiology, Feist-Weiller Cancer Center and 5 PET Imaging Center of the Biomedical Research Foundation of Northwest Louisiana, at Louisiana State University Health Sciences Center, Shreveport, LA; 2 North Texas Clinical PET Institute, Department of Radiology, Baylor University Medical Center, Dallas, TX; 3 US Oncology, Inc., Dallas, TX, USA
* Correspondence to: Dr R. Munker, Division of Hematology/Oncology, Louisiana State University, 1501 Kings Highway, Shreveport, LA 71130, USA. Tel: +1-318-675-8770; Fax: +1-318-675-5944; Email: rmunke{at}lsuhsc.edu
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Abstract |
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Patients and methods: A total of 73 patients with newly diagnosed HD were staged with both conventional methods and whole-body PET scanning. All histological types and stages were represented. The median time of follow-up after the initial diagnosis was 25 months (range 1 month to 5 years). The response to treatment was determined by standard clinical and diagnostic criteria. For the purpose of this analysis, data from a PET center associated with a university medical center and a PET center associated with a group oncology practice were combined.
Results: A total of 21 patients (28.8%) were upstaged by PET compared with conventional methods. In two cases (2.7%), a lower stage was suggested by PET scanning. With one possible exception, the upstaging had no obvious clinical or biological correlate. Among 12 patients in stage I (A + B) by conventional methods, seven were upstaged by PET (58.3%), four to stage II, one to stage III and two to stage IV. Among 42 patients in stage II, eight were upstaged by PET (19.0%), six to stage III and two to stage IV. Among 12 patients in stage III, six (50%) were upstaged to stage IV by PET. If only early-stage patients and major changes are considered (stages IAIIB to III or IV), among 49, 10 were upstaged to III or IV, whereas in 39 staging was unchanged following PET. In the former group, three relapsed or were refractory compared with none in the latter group (P<0.006). In advanced stage patients (IIIA or IIIB) a trend toward treatment failure was apparent in patients who were upstaged by PET.
Conclusions: PET scanning is an interesting new modality for the accurate staging of patients with HD and frequently shows a higher stage than conventional methods. PET should be performed at initial diagnosis and should be included in prospective studies of patients with HD. Upstaging by PET may represent a risk factor for a more advanced stage or a biologically more aggressive tumor. Patients with early-stage disease as identified by conventional methods have a significant risk of treatment failure if a more advanced stage is indicated by PET. At present, major stage changes suggested by PET imaging should be confirmed by an independent diagnostic method.
Key words: Hodgkin's disease, positron emission tomography, staging
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Introduction |
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Patients and methods |
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Follow-up
Patients were seen regularly in clinic and the status of their disease was determined. Patients who were not followed by the institution that started treatment were contacted and asked for health information (general state of health, relapse, treatment complications). In patients who had died, the likely cause of death was determined from medical records. The range of follow-up was 1 month to 5 years; the median time of follow-up from diagnosis was 25 months. In the total series of patients, 66 reached a complete remission or were free from progression if residual abnormalities persisted. Five patients failed the induction treatment and two were not evaluable (one death from a treatment complication and one in whom the induction chemotherapy was not yet finished). The initial response was evaluated after four to six cycles of chemotherapy, if chemotherapy was given. If residual masses persisted, those masses were followed closely and follow-up biopsies obtained if felt clinically necessary; many patients had FDG PET imaging as part of their follow-up and information from that study was also utilized in assessing results of therapy. At last follow-up, six patients had died and five had relapsed after having previously reached complete remission. At last follow-up, one patient had developed a second malignant neoplasm (breast cancer) and one patient had relapsed with a composite lymphoma. Follow-up PET scans were performed in most patients following completion of therapy and at 3- to 6-month intervals.
Statistical analysis
Fisher's exact test was used to test the association between the proportion of changes in stage with different histological subtype, etc. A two-sided P value was used to test our null hypothesis that there is no association. If the P value was <0.05 a statistically significant association was concluded. Survival and freedom from treatment failure were analyzed using KaplanMeier plots.
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Results |
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Discussion |
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Gallium-67 scanning is another method for the metabolic staging of malignant lymphomas, including HD, and has been used for many years in the initial evaluation and more particularly in the follow-up of HD. Gallium imaging has several disadvantages relative to FDG PET, including lower spatial resolution of the scanning technique and lower tumor to background activity levels with resultant poorer image quality. Furthermore, gallium scanning may require up to 1 week to 10 days to complete, compared with FDG PET imaging, which is completed in several hours. Recent data show that the accuracy of gallium scanning compares unfavorably with FDG PET and should therefore no longer be of routine use if FDG PET is available [22].
FDG PET positivity generally indicates a metabolically active tumor, but in some cases the tracer uptake may be non-specific or unrelated to active tumor. According to the literature, many inflammatory or infectious lesions may also show FDG PET positivity; sarcoidosis and some systemic chronic granulomatous infections may be particularly difficult to distinguish from HD based solely on scan appearance [23, 24
]. Since the cellular infiltrate in lesions of HD is composed of tumor cells as well as reactive lymphoid and stromal cells, it is likely that FDG uptake in reactive cells is also, at least in part, responsible for scan positivity. This does not decrease the value of PET scanning at initial diagnosis and for suspected relapse. Another application in later follow-up might be the detection of second malignant tumors in patients with HD.
A potential shortcoming of FDG PET imaging is limited spatial resolution. Microscopic disease (as in limited bone marrow infiltration in patients without obvious signs of marrow compromise) is not evident on PET. On the other hand, FDG PET may show focal marrow infiltration that is not evident or easily assessed by other methods. PET may also occasionally miss a focal site of disease activity in HD, especially in normal sized nodes (as defined by clinical or CT criteria) [16, 17
, 24
]. It is clear, however, that FDG PET may be positive in normal sized but involved nodes by these criteria in a variety of malignancies, well documented in non-small-cell lung cancer [21
]. Different from most cases of HD, low-grade non-Hodgkin's lymphomas may be negative for FDG uptake [25
, 26
].
In our series we describe an interesting biological phenomenon: upstaging by PET may be more frequent in the subtype of mixed cellularity than in nodular sclerosis. This finding needs confirmation. A possible rationale might be that the lesions in the subtype of mixed cellularity are metabolically more active or occur at sites poorly evaluated by CT. The finding does not automatically indicate that disease in this subtype is more widespread or aggressive.
Several authors have suggested that treatment should change according to PET results [14, 16
, 17
, 19
]. To some extent, this may already have happened in clinical practice. However, treatment according to PET positivity under all circumstances is not supported by the presently available data. PET scanning may permit a more accurate diagnosis but major stage changes (e.g. from stage I to stage IV with consequent therapeutic consequences) should be investigated by further diagnostic studies and, if necessary, a biopsy should be performed. According to our data, true stage I may be rare using a sensitive method like PET scanning.
A diagnostic test is only clinically useful if the results indicate particular clinical features, predict the treatment outcome or correlate with other established diagnostic tests. Therefore, FDG PET scanning at initial diagnosis should be included in prospective studies of HD. It is reasonable to assume that upstaging by PET is an indicator of more widespread disease and of worse prognosis. Upstaging by PET may be a risk factor like increased levels of soluble CD30, sedimentation rate and ß2-microglobulin [27, 28
]. As mentioned previously, a further use of pretreatment PET scanning may be in better planning of radiotherapy ports and in the choice of patients for different treatment approaches such as up-front high-dose therapy or immunotherapy. However, these uses of PET should be validated by clinical studies. In the future, technical advances like new tracers other than FDG, perhaps with greater specificity, scanners with improved spatial resolution, and scanners that combine PET and CT may further enhance the value of PET in the initial diagnosis and follow-up of patients with HD.
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Acknowledgements |
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Received for publication March 23, 2004. Accepted for publication June 16, 2004.
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References |
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