Departments of 1 Clinical Oncology 2 Haematology and 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: +44 207 188 4219; Email: george.mikhaeel{at}gstt.nhs.uk
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Abstract |
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Patients and methods: One hundred and twenty-one patients with high-grade NHL underwent FDG-PET. The therapy response on FDG-PET was correlated to PFS and OS using KaplanMeier survival analysis. Cox regression analyses were employed to test for independence of known pretreatment prognostic factors.
Results: Fifty FDG-PET scans were negative, 19 scans showed minimal residual uptake (MRU), and 52 scans were positive. The estimated 5 year PFS was 88.8% for the PET-negative group, 59.3% for the MRU group, and 16.2% for the PET-positive group. KaplanMeier analyses showed strong associations between FDG-PET results and PFS (P <0.0001) and OS (P <0.01). Early interim FDG-PET was independent of the other prognostic factors.
Conclusions: Early interim FDG-PET is an accurate and independent predictor of PFS and OS. An early assessment of chemotherapy response with FDG-PET could provide the basis for selection of patients for alternative therapeutic strategies.
Key words: fluorodeoxyglucose F18, non-Hodgkin lymphoma, positron emission tomography, prognosis
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Introduction |
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The prognosis in HG-NHL is most commonly established on the basis of histopathological subtype and the clinical characteristics in the International Prognostic Index (IPI); clinical disease stage, age, performance status, number of affected extranodal sites, and serum lactate dehydrogenase concentration [3]. IPI is a well-established predictor of treatment outcome but there is considerable variation between the outcomes of individual patients within the same IPI prognostic group. Response to treatment is another predictor of outcome, which has the advantage of guiding the management decision for the individual patient. The monitoring of treatment efficacy is generally performed with sequential evaluations of tumour size using anatomical imaging modalities, most commonly computerised tomography (CT). CT cannot distinguish between a viable tumour mass and residual scar tissue. Equally important, assessment of response is not reliable early on during treatment since tumour volume reduction takes time.
Positron emission tomography with 2-[18F]fluoro-2-deoxy-D-glucose (FDG-PET) performed early during the course of chemotherapy has in recent years been recognised as a strong predictor of outcome. Published data suggest that complete response (CR) is readily evident on FDG-PET after two to three cycles and that such early CR on FDG-PET confers a favourable prognosis. However, the studies published so far are all based on relatively small numbers of patients, and some include patients with Hodgkin's lymphoma (HL), which has a much higher response rate and better overall prognosis [48
]. This study aims to investigate the prognostic value of an early interim FDG-PET scan in a large cohort of HG-NHL patients.
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Patients and methods |
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PET scans
18F-FDG was produced from an onsite 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 approximately 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 muscle/brown fat uptake of the tracer. Images were displayed as whole body projections and as transaxial, coronal and sagittal tomographic sections. When indicated, localised images were produced with attenuation correction. Two experienced nuclear medicine physicians read all scans, and differences were decided by consensus. Interim FDG-PET results were scored as either negative, minimal residual uptake (MRU), or positive [7]. Negative was defined as the disappearance of all abnormal disease-related uptake. MRU was defined as low-grade uptake of FDG in a focus within an area of previously noted disease, reported by the nuclear medicine physicians as likely to represent inflammation but where small volume malignancy could not be excluded. Positive was defined as the persistence or appearance of new areas of increased uptake, thought to be lymphoma-related. PET data were scored with no knowledge of the clinical outcome of treatment.
Statistical analysis
Progression-free survival (PFS) and overall survival (OS) were chosen as end points. 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 was censored at other causes of death or if the patients were free of progression/relapse at last 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 applied to assess the effects of the relevant prognostic factors on the survival times and the independency 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. Confidence intervals were given as 1.96 x standard 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) [9, 10
].
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Results |
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Of the nine patients with primary refractory disease, eight had positive early interim FDG-PET and one had MRU. Forty patients with initial response to therapy later relapsed. Fifteen of the patients who died came from the FDG-PET positive group. Only two patients from the PET-negative group died. In the 49 patients with progression, 37 were from the FDG-PET positive group, seven had MRU and five had been FDG-PET negative. These distributions are shown in Figure 2.
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Figure 3 shows the survival plots depicting PFS and OS, respectively. Log-rank tests with P <0.0001 for PFS and P <0.01 for OS demonstrated that the differences between the curves of response groups according to FDG-PET are statistically highly significant. A multivariate Cox regression analysis of PFS was performed, including the following variables: presence of B symptoms, extranodal disease, bulky disease, clinical disease stage, age at diagnosis and early interim PET. The model showed that the value of FDG-PET for prediction of PFS was independent of the other factors (2, P<106). The model showed that early response on FDG-PET was by far the most influential of the independent variables. Clinical stage also showed significant independent contributions to the model (
2, P<0.01). In a different model, clinical stage was included as a stratifying variable rather than as an independent covariate. This is arguably more appropriate, since the clinical stage is the most important determinant of treatment. In this model, the interim FDG-PET result proved to be the only independent predictor of PFS (
2, P <105). A Cox regression model with the same variables was fitted for OS (Table 2); similar conclusions were reached. Response on interim FDG-PET and clinical stage proved to be the strongest variables with independent prognostic value, and again FDG-PET was by far the stronger of the two (
2, P <0.05 for PET and P <0.1 for stage). With clinical stage as a stratifying variable, interim PET was the only variable with independent predictive value (
2, P <0.05). An overview of the results of the regression models is given in Tables 2 and 3.
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Discussion |
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Therefore, in order for treatment intensification to improve outcome, reliable prognostic indicators are required, to identify those patients who would benefit from intensive treatment strategies and those who could be cured with less intensive and less toxic treatment [17]. At present, the risk stratification is usually based on a number of prognostic factors included in the IPI [3
]. The IPI takes into account pretreatment characteristics only, although, for the individual patient, the response to treatment is probably the single most important determinant of outcome. Armitage et al. [18
], showed that patients with an early response to induction therapy are more likely to enter a lasting remission. Response is usually assessed by CT. Since CT does not differentiate between a viable tumour mass and residual scar tissue, it has limited value in assessing the degree of response [19
].
Molecular imaging reflects the metabolic activity rather than the size of tissue masses. Furthermore, metabolic changes during therapy tend to precede the anatomical changes and this allows for earlier and perhaps more effective changes of therapy. It is well recognised that an early treatment change in patients who fail to respond to treatment is beneficial [20]. The concept of molecular imaging for prediction of treatment response in NHL is not a new one. There is good evidence that a gallium-67 scan after one to two cycles of chemotherapy has high specificity and is a much better predictor of treatment failure than CT. However, the sensitivity is rather low since the method fails to identify a large number of non-responders. Furthermore, gallium scans are laborious procedures for both the patient and the clinic, with a high radiation burden for the patient [21
24
].
The value of an interim FDG-PET performed early during treatment in NHL has been addressed in a number of smaller studies. Hoekstra et al. [4] presented the first report suggesting a role for FDG in the early monitoring of lymphoma therapy in 1993. Thirteen NHL patients were examined after two courses of chemotherapy with a planar gamma camera. Negative scans preceded complete remission in seven of 13 patients and abnormal uptake preceded treatment failure or death in four patients. A previous investigation by our group demonstrated the prognostic properties of an early interim FDG-PET after two to three cycles of chemotherapy on 23 HG-NHL patients [7
]. In their study of 28 heterogenous NHL patients, Jerusalem et al. [5
] found significantly better short-term disease-free survival among the patients who were FDG-PET-negative after two to five cycles of chemotherapy. These studies indicate a strong predictive value of an interim FDG-PET, but they are based on small numbers and short follow-up. The largest previous investigation so far of the predictive value of an interim FDG-PET was published by Spaepen et al. [25
]. They examined 70 HG-NHL patients and found a highly significant association between the mid-treatment FDG-PET findings and the PFS and even OS. Multivariate analysis by Cox regression showed that FDG-PET was a stronger prognostic factor for both PFS and OS than the International Prognostic Index (IPI) and independent of its separate elements [3
].
In the current study, with 121 patients and a median follow-up of 28.5 months (range 3101), KaplanMeier analyses showed highly significant associations between the early interim FDG-PET results and PFS (P <0.0001) and OS (P <0.01). The multivariate survival analyses proved FDG-PET to be independent of the other prognostic factors and to have stronger predictive value than any of these. In 37 out of 52 PET-positive patients who had disease progression within the follow-up period, the average time from the early interim FDG-PET to first objective sign of progression with conventional methods was 9.6 months. The very high relapse rate in the interim FDG-PET-positive group has a significant clinical implication and suggests that an early change in therapy is indicated in these patients. It is worth noting that the high relapse rate was consistent in early and advanced stages (Figure 4). However, the benefit of early treatment intensification needs to be assessed in randomised controlled trials.
The optimal timing of the interim scan is not clear. It is obviously desirable to assess response and predict prognosis as early as possible. Kostakoglu et al. [6] found FDG-PET after just one cycle of chemotherapy to be a strong predictor of relapse, but follow-up was quite short and the 17 HG-NHL patients were not analysed separately from the 13 HL patients in the study. Römer et al. [8
] examined 11 NHL patients at baseline and at days 7 and 42 after initiation of chemotherapy. They found quantitative measures of FDG uptake reduced at day 7 (after one cycle) and further reduced at day 42 (after two cycles), but only the scan after two cycles had significant predictive value. With current chemotherapy schedules, we consider the highest value of an interim FDG-PET is achieved after two cycles of chemotherapy. Due to practical reasons, however, a fraction of the patients included in this study could not be scanned until after the third cycle of chemotherapy.
As in earlier investigations from our group, we chose not to score PET results exclusively as either positive or negative, but as either clearly positive or negative, or belonging to a group with MRU. The reason for this approach was to reflect the daily life in the lymphoma clinic where a certain number of FDG-PET scans are reported to the clinicians as neither clearly positive nor negative. Interestingly, the survival curves in Figure 4 where early and advanced stage patients are displayed separately show that regarding PFS and OS, MRU patients behave like PET-negative patients in the early stages and like PET-positive patients in the advanced stages. One possible explanation is the routine use of involved-field radiotherapy in stage 1 and 2 patients, which might have eradicated small-volume residual disease represented by a low-grade FDG uptake on the interim scan.
The flow charts in Figure 6 indicate that an end-of-treatment FDG-PET does not provide more prognostic information to an early interim FDG-PET that is either clearly positive or negative. On the other hand, where interim FDG-PET results were uncertain (MRU), end-treatment PET seemed a valid predictor of the prognosis, although the numbers were too small for any firm conclusions to be drawn.
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However, our results represent the most substantial body of evidence so far of the value of an early interim FDG-PET scan for prediction of PFS and OS in HG-NHL patients. The Cox regression analyses displayed in Table 2 show early interim FDG-PET to be correlated stronger with PFS and OS than any of the important pretreatment prognostic factors, and independent of all these.
The relatively high number of patients in our study allowed for a subgroup analysis of the 75 patients with diffuse large B-cell lymphoma. Within this more homogenous subgroup, FDG-PET still had a significant value for prediction of PFS and OS (Figure 5) and survival curves are almost identical to those of the whole group (Figure 3).
Despite the strong prognostic value of early interim FDG-PET, there are still a few PET-negative patients who experience progression, especially with advanced stage. As our data showed that the prognostic value of early response on interim PET was independent from other prognostic factors, a logical extension of the use of interim PET would be to combine it with the IPI to see if together they enhance the estimation of long-term prognosis. Unfortunately, this was not possible in our retrospective cohort, as the IPI score was not always recorded. On the other hand, there is a range of biological factors, measurable with immunohistochemistry, polymerase chain reaction or microarrays, that are increasingly proving to be predictive of outcome in high-grade lymphoma including BCL2, BCL6 and CD10 [2628
]. It is possible that one or more of these factors, in conjunction with FDG-PET as an early measure of therapy response, could provide a basis for the selection of patients for treatment adaptation. Other developments in functional imaging may also prove to be useful. The introduction of PET/CT scanners may further improve the evaluation of treatment response. New tracer developments may provide a means of monitoring proliferation, using F-18 fluorothymidine, or chemotherapy-induced apoptosis with 99mTc-labelled Annexin V, which in early investigations has proved to be a predictor of tumour response to therapy as early as 1 day after administration of the first cycle of chemotherapy [29
].
In conclusion, early interim FDG-PET offers a unique tool for early prediction of long-lasting CR and PFS as well as OS in patients with HG-NHL. The predictive value of early interim FDG-PET is stronger than many of the known pretreatment prognostic factors and is independent of these. If new therapy regimens include early treatment intensification for selected high-risk patients, who are unlikely to be cured with conventional chemotherapy, early interim FDG-PET could play an important role in the selection of these patients.
Received for publication January 17, 2005. Accepted for publication April 13, 2005.
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