1 Department of Clinical Oncology, 2 Department of Haematology, 3 The Clinical PET Centre, Guy's and St. Thomas Hospital, London, UK
* Correspondence to: Dr N. G. Mikhaeel, Department of Clinical Oncology, Lambeth Wing, St. Thomas Hospital, London SE1 7EH, UK. Tel: +44-(0)207-188-4219; Fax: +44-(0)207-928-9968; Email: george.mikhaeel{at}gstt.nhs.uk
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Abstract |
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Patients and methods: A total of 85 patients with HL underwent FDG-PET after two or three cycles of chemotherapy. Median follow-up was 3.3 years. FDG-PET results were related to PFS and OS using KaplanMeier analysis. Regression analyses were employed to test for independence of established pretreatment prognostic factors.
Results: After two or three cycles of chemotherapy, 63 patients had negative FDG-PET scans, nine patients had minimal residual uptake (MRU) and 13 patients had positive scans. Three PET-negative patients and one patient from the MRU group relapsed. In the PET-positive group, nine patients progressed and two died. Survival analyses showed highly significant associations between early interim FDG-PET and PFS (P <0.0001) and OS (P <0.03). All advanced-stage patients with positive interim FDG-PET relapsed within 2 years.
Conclusion: Early interim FDG-PET is an accurate and independent predictor of PFS and OS in HL. A positive interim FDG-PET is highly predictive of relapse in advanced-stage disease.
Key words: fluorodeoxyglucose F18, Hodgkin lymphoma, positron emission tomography, prognosis
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Introduction |
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CT scanning has significant limitations in assessing response to treatment. Functional imaging with positron emission tomography using 2-[18F]fluoro-2-deoxy-D-glucose (FGD-PET) has gained increasing acceptance as a staging procedure in HL [46
]. In recent years, a number of studies have been published showing a strong predictive value of an early interim FDG-PET scan in high-grade non-Hodgkin lymphoma (HG-NHL) patients [7
12
]. Four of these studies included small subgroups of HL patients who have been analysed as parts of larger mixed lymphoma populations [10
13
]. In 1993, Hoekstra et al. reported a subgroup of 13 HL patients scanned with planar FDG scintigraphy [10
] and later Kostakoglu et al. examined a subgroup of 13 patients with dual-headed coincidence gamma-camera FDG-PET after one cycle of chemotherapy [11
]. A third study included only three HL patients [12
]. More recently, in 2004, Friedberg et al. [13
] published a study in which 22 de novo HL patients were FDG-PET scanned after three cycles of chemotherapy. After a median follow-up of 24 months, four out of five interim FDG-PET-positive patients had progressed and 15 out of 17 FDG-PET-negative patients were in continued remission. These studies suggested that an early FDG-PET is predictive of complete response and superior to FDG-PET after completion of treatment for prediction of disease progression.
Since HL and HG-NHL have very different treatment strategies and response rates, the value of prognostic tools for the two entities should ideally be assessed separately [14]. This study aims to assess the prognostic value of interim PET after two or three cycles of chemotherapy in HL.
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Materials and methods |
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PET scans
All scans were performed within the second week of the interval between ABVD treatments or as late as possible before administration of the next chemotherapy cycle. [18F]FDG was produced from an on-site cyclotron and chemistry facility. All PET scans were performed as half-body scans (mid-brain to upper thigh) after a 6 h fast. Emission data were acquired for 5 min per bed position, starting 60 min after intravenous injection of 350 MBq [18F]FDG, using an ECAT 951R dedicated PET scanner (Siemens/CTI, Knoxville, TN). Diazepam was given orally to some patients before FDG administration to avoid muscular uptake of the tracer. Images were displayed as whole-body projections and as transaxial, coronal and sagittal tomographic sections. When indicated, higher-resolution localised images were produced with attenuation correction. Two experienced nuclear medicine physicians read all scans, and differences were decided by consensus. As in earlier publications, interim PET results were scored as negative, minimal residual uptake, or positive [8
]. Negative was defined as no evidence of disease. Minimal residual uptake was defined as low-grade uptake of FDG (just above background) in a focus within an area of previously noted disease reported by the nuclear medicine physicians as not likely to represent malignancy. Positive was defined as increased uptake suspicious for malignant disease, which did not have a benign explanation.
Statistical analysis
For the study of the prognostic effect of interim FDG-PET, progression-free survival (PFS) and overall survival (OS) were chosen as endpoints. PFS was defined as the time from diagnosis to first evidence of progression or relapse, or to disease-related death. OS was defined as the time from diagnosis to death from any cause. Data were censored at other causes of death or if the patients were free of progression/relapse at follow-up. Survival was depicted using KaplanMeier plots. Differences between groups were analysed using the log rank test. Proportional survival at certain times was determined using life-table statistics. Multivariate proportional hazards (Cox) regression analysis was used to assess the effects of the relevant prognostic factors on the survival times and the independence of these variables (backward Wald stepwise procedure). Schoenfeld and Martingale residuals plots were employed to check for assumptions of proportional hazards and linearity. The plots were evaluated visually with the help of locally weighted regression fits (lowess curves). Confidence intervals were given as 1.96xstandard error of the mean. Tests were two-sided with 5% as the level of significance. All data analyses were performed using the statistical software package SPSS 12.0 (SPSS Inc., Chicago, IL) [15, 16
].
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Results |
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During the variable follow-up periods, 12 patients showed disease progression or relapse. Of these, three patients failed to reach a satisfactory remission during initial chemotherapy, leading to a change from the original treatment plan to alternative therapy. Secondary treatment was MOPP (mechlorethamine, vincristine, procarbazine, prednisolone), BEAM (carmustine, etoposide, cytarabine, melphalan) plus stem cell transplant and BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisolone). Two of the three patients with such primary refractory disease later died, accounting for all deaths in the study group. Both deaths were HL related. The remaining nine patients achieved remission with initial treatment but relapsed later. Of the 12 patients with relapsed disease, eight were from the PET-positive group, one had minimal residual uptake and three had a negative interim PET. This distribution is displayed in Figure 2. The figure represents censored data and the times from diagnosis to last follow-up vary markedly. Thus the bar chart is for overview only and no statistical analysis was applied. However, it shows that most patients with negative scans and minimal residual uptake survived the follow-up period without relapse, whereas a majority of the PET-positive patients experienced disease relapse. The time from the interim PET scan to the recognition of progression with conventional methods was 121 months (mean 9.0 months) for the eight PET-positive patients and 1233 months (mean 24.3 months) for the three PET-negative patients (two-tailed t-test, P <0.05).
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Discussion |
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In both early and advanced HL, the concept of risk-adapted therapy is becoming very important to achieve high cure rates with minimal long-term morbidity and mortality. While prognosis can be estimated using well-established and validated prognostic indices [1], response to treatment is probably the most important single prognostic factor for the individual patient. In the work reported in this paper we examined the ability of FDG-PET to assess early response during treatment accurately and to predict long-term outcome.
Overall analysis of our patient cohort regarding distributions of patient age, histology, stage, and other clinical characteristics shows no remarkable differences from standard literature [17]. No significant difference in PFS was found between the HL patients who had interim FDG-PET and the rest of patients treated in our clinic who did not have interim FDG-PET (log rank, P=0.697) (Figure 1).
Our results show that the majority of patients had an excellent response early in treatment (63 negative and nine MRU out of total of 85), reflecting the chemosensitivity of the disease. The ability of FDG-PET to assess response early is particularly important for shortened treatment regimes in early stage disease. Early response on FDG-PET was predictive of long-term outcome. The projected 5-year PFS for PET-negative patients (including MRU) was 91.5% compared with 38.5% for PET-positive patients. The difference is statistically significant. Equally important, the mean times to relapse were 24.3 months and 9 months for the PET-negative and PET-positive groups, respectively. It is well recognized that relapse within 1 year has a worse prognosis than later relapse [27]. Interim FDG-PET is shown to be a stronger prognostic factor for prediction of PFS than any of the other important pretreatment prognostic factors, and independent of clinical stage on multivariate analysis.
Compared with HG-NHL, interim FDG-PET in HL seems to have a similar negative predictive value but a lower positive predictive value. Data from our group on 121 patients with HG-NHL showed projected 5-year PFS of 88.8% and 16.2% for PET-negative and PET-positive groups, respectively [28]. This difference is probably a reflection of the generally more favourable outcome of HL. Different groups have shown a high positive predictive value for interim FDG-PET in HG-NHL [7
, 9
]. Other investigators have also shown a lower positive predictive value for FDG-PET in HL compared with HG-NHL when used to assess end-of-treatment remission status [29
31
]. There are very few data on interim FDG-PET in HL in the literature.
We examined the predictive value of interim FDG-PET in early compared with advanced stage HL. While the KaplanMeier plots showed statistically significant differences between PET-negative and PET-positive patients in both groups, the prognostic significance of the FDG-PET result was different. Of interest, the majority of patients with early stage and positive interim FDG-PET remained in remission for the duration of follow-up. In contrast, all patients with advanced stage and a positive interim FDG-PET relapsed within 2 years. These findings have very important clinical implications and clinicians need to be aware of them. Early stage patients with positive interim FDG-PET may continue on treatment and be followed up closely for relapse. Advanced stage patients who fail to achieve FDG-PET negativity after two or three cycles have a much worse prognosis, with the majority destined to relapse within 2 years. This may form the basis for an early change in therapy.
As in previous reports from our group, we scored the scan results as either clearly positive or negative, or as belonging to a group with minimal residual uptake. In our view, this better reflects the clinical practice where a number of FDG-PET scans are not reported as either clearly negative or positive. It is well known that a large part of the tumour in HL consists of inflammatory cells, which may take up FDG. Chemotherapy-induced apoptosis can also trigger an inflammatory response. These factors may account for some non-malignant residual low-grade FDG uptake. The analysis of our data shows that the highest predictive value is achieved when interim scans with MRU are counted as negative scans.
The flowcharts in Figure 6 indicate that an FDG-PET after end of treatment does not add prognostic information to an early interim FDG-PET which was clearly positive or negative. Indeed, the two interim FDG-PET-negative patients who had positive end-of-treatment FDG-PET scans were still without relapse at the time of last follow-up. Among the interim FDG-PET-positive patients, the rate of relapse was equally high among those with positive and negative end-of-treatment scans. On the other hand, where interim FDG-PET showed MRU, end-of-treatment FDG-PET predicted the prognosis successfully. However, the numbers of patients who had end-of-treatment FDG-PET is relatively small, limiting the ability to draw solid conclusions.
In summary, interim FDG-PET offers a reliable method for early prediction of long-term remission and progression-free survival in HL. Interim FDG-PET, in combination with stage, is able to identify patients at high risk of relapse who are potential candidates for more intensive treatment. With the increasing interest in risk-adapted treatment strategies, early FDG-PET after two or three cycles of chemotherapy could potentially be used as a tool to stratify risk and predict prognosis to aid treatment modification. Such modifications should be tested in randomized controlled trials. An example of such a trial is the current UK early HL trial testing the omission of involved field radiotherapy for patients achieving PET negativity after chemotherapy.
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Acknowledgements |
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Received for publication March 21, 2005. Accepted for publication March 24, 2005.
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