Early detection of relapse by whole-body positron emission tomography in the follow-up of patients with Hodgkin’s disease

G. Jerusalem1,+, Y. Beguin1, M. F. Fassotte1, T. Belhocine2, R. Hustinx2, P. Rigo2 and G. Fillet1

1 Department of Medicine, Division of Medical Oncology and Hematology and 2 Division of Nuclear Medicine, University of Liège, Liège, Belgium

Received 18 February 2002; revised 4 June 2002; accepted 17 July 2002


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:

Relapse after treatment of Hodgkin’s disease (HD) is usually identified as a result of the investigation of symptoms. We undertook this study to examine the value of whole-body positron emission tomography (PET) for the detection of preclinical relapse.

Patients and methods:

Thirty-six patients underwent 2-[fluorine-18]fluoro-2-deoxy-D-glucose (18F-FDG) PET at the end of treatment and than every 4–6 months for 2–3 years after the end of polychemotherapy and/or radiotherapy. In those cases of abnormal 18F-FDG accumulation a confirmatory study was performed 4–6 weeks later.

Results:

One patient had residual tumor and four patients relapsed during a follow-up of 5–24 months. All five events were correctly identified early by 18F-FDG PET. Residual tumor or relapse was never first diagnosed based on clinical examination, laboratory findings or computed tomography (CT) studies. Two patients presented B symptoms and the three others were asymptomatic at the time of residual disease or relapse. Confirmation of residual disease or relapse was obtained by biopsy in four patients 1, 1, 5 and 9 months after PET and by unequivocal clinical symptoms and CT studies in one patient 3 months after PET. False-positive 18F-FDG PET studies incorrectly suggested possible relapse in six other patients, but the confirmatory PET was always negative. Our study also provides important information about physiological 18F-FDG uptake in the thymus.

Conclusions:

Our data suggest the potential of 18F-FDG PET to detect preclinical relapse in patients with HD. This could help identify patients requiring salvage chemotherapy at the time of minimal disease rather than at the time of clinically overt relapse. Further studies are warranted to determine the impact of PET on treatment management and outcome. In fact, the aim of follow-up procedures is not only to detect preclinical relapse but mainly to obtain better results by starting salvage treatment earlier. A cost–benefit analysis will also be necessary before 18F-FDG PET can be used routinely in the follow-up of patients with HD.

Key-words: 2-[fluorine-18]fluoro-2-deoxy-D-glucose, follow-up, Hodgkin’s disease, positron emission tomography, radionuclide imaging, relapse


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Positron emission tomography (PET) using 2-[fluorine-18]fluoro-2-deoxy-D-glucose (18F-FDG) has emerged as a clinical method for staging and monitoring responses to treatment in a variety of cancers [1]. Encouraging results have been reported in Hodgkin’s disease (HD) and non-Hodgkin’s lymphoma (NHL) for the initial staging [211] and for re-evaluation during or at the end of treatment [10, 1221]. HD is highly responsive to both radiation and chemotherapy. Relapse occurs in about 20–30% of the patients, usually in the first 3 years after treatment. The relapse rate is maximal 12–18 months after the start of treatment but declines rapidly thereafter [22]. Early diagnosis of disease recurrence may be important for successful treatment, before the tumor load is too large. Relapse is usually identified as a result of the investigation of symptoms rather than by routine screening of asymptomatic patients [22], although regular radiological studies may be useful. The purpose of this study was to examine the value of whole-body 18F-FDG PET for the detection of preclinical relapse in the follow-up of patients with HD for 2–3 years starting at the end of treatment work-up. We also analyzed the rate of false-positive PET studies as well as the physiological 18F-FDG uptake in the thymus.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients
Thirty-six consecutive patients with histologically verified HD were included prospectively in our study between June 1994 and January 1999. Patient characteristics are listed in Table 1. All patients gave oral informed consent for the PET study, which was considered as a routine procedure in their follow-up.


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Table 1. Patient characteristics
 
Follow-up
One month after treatment we evaluated the response to treatment by computed tomography (CT) and by 18F-FDG PET. Thereafter, the patients underwent follow-up visits at least every 4 months for 2 years then every 6 months the third year after completion of therapy. Routine follow-up methods included clinical examination and laboratory screening. Most patients also underwent radiological studies (chest X-ray, CT) at the discretion of the clinician. 18F-FDG PET studies were performed every 4–6 months for 2–3 years after the end of polychemotherapy and/or radiotherapy.

18F-FDG PET studies
Whole-body PET using 18F-FDG was performed with a Penn Pet 240-H Scanner (UGM, Philadelphia, PA, USA). 18F-FDG was produced using an automated synthesizer marketed by the Coincidence Company (Liège, Belgium). Two to three hundred megabecquerels of 18F-FDG were administered intravenously and emission scans were recorded 50–90 min later. All patients were asked to fast for at least 6 h before the study. A whole-body acquisition was performed from the cervical to the inguinal region. It consisted of 10–12 separate overlapping acquisitions each covering 12.8 cm and performed during 4 min. Each subsequent acquisition was performed after a 6.4 cm displacement of the table. The total time of image acquisition was about 50 min. Images were reconstructed using filtered back projection with a Hanning filter (50 of 119 studies) or more recently (since 1997) by iterative reconstruction (69 of 119 studies). Images were reconstructed in transverse, coronal and saggital planes. A 4 mm voxel size was used. Isotropic three-dimensional resolution was better than 8 mm. Interpretation was performed in a qualitative manner without attenuation correction in 68 18F-FDG studies. More recently, transmission scans with attenuation correction were performed in 51 18F-FDG PET studies. Furosemide (20 mg in slow intravenous injection) was administered to enhance 18F-FDG urinary elimination. Diazepam (5 mg) was given orally before 18F-FDG administration to prevent muscular uptake.

Interpretation of 18F-FDG PET studies
All PET images were analyzed by a physician in the division of nuclear medicine and then reviewed by one investigator (G. J.). Any focus of increased 18F-FDG uptake over background not located in areas of physiological 18F-FDG uptake (central nervous system, heart, digestive tract, thyroid gland, muscles), in the thymus (post-treatment reactive thymic hyperplasia) and/or in the urinary tract (18F-FDG excretion) was considered positive for tumor. Post-treatment 18F-FDG PET scans were first interpreted without knowledge of clinical, CT or previous PET data. In the case of abnormal 18F-FDG uptake, we then correlated our findings with clinical information and CT studies. Indeed, strong 18F-FDG uptake is not only observed in malignant tissue, but can also be seen in inflammatory lesions (sarcoidosis, tuberculosis, fungal infections, abdominal abscesses etc.). We thus considered that the abnormal 18F-FDG uptake was related to tumor relapse, except when the clinical data clearly indicated uptake in non-malignant lesions. When relapse suspected by PET studies was not confirmed by conventional staging procedures and/or biopsy, a confirmatory study was performed 4–6 weeks later.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Three hundred and nineteen clinical examinations were performed (median per patient: five in the first year, three in the second year and two in the third year). Laboratory tests were obtained at most clinical visits (285 of 319). Most patients also underwent radiological studies (chest X-ray: 64 studies, median one per patient; CT: 114 studies, median three per patient). One hundred and nineteen 18F-FDG PET studies were performed (median three per patient, range one to eight).

At the end of treatment, conventional procedures indicated residual masses in 19 patients and complete remission without residual masses in 17 patients. Eleven patients presented a positive 18F-FDG PET study, one at the end of treatment evaluation and the others at later times during follow-up. The results of post-treatment CT studies and of 18F-FDG PET during follow-up after treatment are summarized in Figure 1. All conventional studies carried out before 18F-FDG PET were negative or showed unchanged residual masses. In five of them, relapses were later confirmed and details are given in Tables 2 and 3. These included the one patient positive at the end of treatment evaluation and four patients who became positive 5, 7, 20 and 24 months thereafter. Three of these five patients had presented residual masses detected by CT at the end of treatment. Two patients presented B symptoms (unexplained fever >38°C, night sweats, unexplained weight loss >10% body weight) and the three others were asymptomatic at the time of relapse. The relapse was confirmed by biopsy in four patients 1, 1, 5 and 9 months after PET and by unequivocal clinical symptoms and CT studies in one patient 3 months after PET. An example of a relapse detected early by PET is illustrated in Figure 2.



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Figure 1. Clinical outcome according to the results of computed tomography (CT) at the end of treatment and positron emission tomography (PET) during follow-up.

 

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Table 2. Relapses detected by 18F-FDG PET
 

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Table 3. Confirmation of residual tumor or relapse in patients with positive 18F-FDG PET studies
 


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Figure 2. 2-[Fluorine-18]fluoro-2-deoxy-D-glucose positron emission tomography suggested a mediastinal relapse in an asymptomatic patient 9 months (A) and 3 months (B) before histological confirmation (patient no. 2, see Tables 2 and 3).

 
In the six other cases, relapse was not confirmed, i.e. confirmatory 18F-FDG PET and/or CT studies of the six false-positive patients were always negative. An example of false-positive PET is illustrated in Figure 3. The reasons for false-positive studies remain unknown, but we believe that 18F-FDG accumulation may be related to an atypical thymic uptake or digestive tract uptake in most patients. One patient had a proven toxoplasmosis. Technical conditions do not explain the false-positive studies since four of six false-positive PET studies were done with attenuation correction (Table 4).



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Figure 3. False-positive 2-[fluorine-18]fluoro-2-deoxy-D-glucose positron emission tomography study in the mediastinum, probably due to atypical thymic uptake (patient no. 33, see Table 4).

 

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Table 4. False-positive 18F-FDG PET uptake
 
Finally, two patients later came back to the clinic because they had noticed enlarged lymph nodes by self-examination. In another patient, the clinician suspected a relapse. Lymph node biopsies and follow-up studies (including PET) remained negative and all three patients remain in clinically complete remission.

As five events have been correctly identified by PET in 119 studies, the total cost of PET studies to detect one residual tumor or relapse was ~$18 000 (one PET = $750). As two patients also had B symptoms at the time of relapse, the total cost of PET to detect one asymptomatic residual tumor or relapse was $30 000. The overall costs for all imaging studies are even higher because false-positive PET scans resulted in additional CT studies.

Table 5 shows the incidence and localization of physiological 18F-FDG uptake observed in our study. The frequency of thymic uptake (23 of 119 studies) is of particular interest. Seventeen of 74 PET studies (23%) in the first year but also six of 29 PET studies (21%) in the second year after treatment demonstrated thymic uptake. An example of thymic uptake is illustrated in Figure 4.


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Table 5. Physiological 18F-FDG uptake
 


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Figure 4. Physiological 2-[fluorine-18]fluoro-2-deoxy-D-glucose uptake in the thymus 5 months after completion of polychemotherapy.

 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Intensive follow-up evaluation for diseases such as breast or non-small-cell lung cancer is of questionable value because these tumors are generally incurable once metastases develop and early detection of relapse is unlikely to result in increased survival. In contrast, salvage therapies for recurrent HD are effective in many patients, justifying closer follow-up observation. Unfortunately, evidence-based recommendations for the follow-up of patients after curative therapy for HD are lacking. Although it is routine for patients to return to the clinic on a regular basis for clinical examination, laboratory tests and radiological studies, only a few reports have been published about the value of such follow-up procedures [2225] and no randomized trials are available. Routine follow-up after treatment of HD also plays several other functions, such as patient reassurance and detection of late side-effects of chemotherapy and radiotherapy, including secondary tumors [22, 23]. Three-monthly visits in years 1 and 2, 4-monthly visits in year 3, 6-monthly visits in years 4 and 5, and annual visits thereafter are recommended by the Cotswold Committee [26]. The frequency and type of radiological studies should reflect the initial sites of disease. Appropriate investigations should be performed when there is any concern about symptoms or signs of possible disease recurrence.

We present the first study evaluating prospectively the role of 18F-FDG PET in the routine follow-up of patients after treatment of HD. The results indicate that 18F-FDG PET may be useful to identify a relapse in asymptomatic patients or in symptomatic patients with equivocal radiological studies. These results contrast with those published in the literature for conventional radiological procedures, which indicate that clinical symptoms are generally present before the relapse of HD is identified [22, 23]. This is even more the case with large-cell lymphoma where only 6% of relapses are detected before the development of symptoms [27].

Radford et al. [22] examined the effectiveness of standard routine follow-up in detecting relapse after treatment of HD. The frequency of follow-up visits was 2-monthly in year 1, 3-monthly in year 2, 4-monthly in year 3, 6-monthly in years 4 and 5, and yearly thereafter. Blood was drawn for complete blood counts, erythrocyte sedimentation rate and a serum biochemical profile, and if the patient had mediastinal disease at presentation a chest radiograph was obtained. The authors analyzed the number of clinic visits made by the patients over the period of observation, the number of relapses occurring during that time, and the means by which relapse was detected. A total of 210 patients generated 2512 outpatient visits and 37 relapses were detected (one relapse was detected every 68 visits). A peak of 10 or 11 events per 100 patients yearly occurred 12–18 months after the start of treatment with a rapid decline to about five relapses per 100 patients yearly by year 3 and a further fall to fewer than two relapses per 100 patients yearly by year 5. Thirty relapses (81%) were diagnosed in patients who described symptoms. In only half of these cases had an earlier appointment been arranged by the patient based on these symptoms, illustrating the need for better patient education. Routine physical examination or investigation of an asymptomatic patient identified a relapse in only four cases (11% of all relapses).

Torrey et al. [23] examined the costs and benefits of routine follow-up evaluation in patients treated with radiation therapy for early stage HD. Relapse occurred in 157 of 709 patients (22%) at a median of 1.9 years (range 0–13 years) after treatment. Relapse was suspected primarily by symptoms in 55% of the patients, physical examination in 14%, chest X-ray in 23% and abdominal X-ray in 7%. Friedman et al. [28] determined that the rate of relapse detection was highest and the cost lowest (in 1995 dollars) for a combination of history and physical examination (78 of 10 000 examinations, $11 000 per relapse) compared with chest X-ray (26 of 10 000 examinations, $68 000 per relapse). However, some relapses were diagnosed only by chest X-rays. The 10-year survival rate following salvage therapy was equivalent (65% and 69%, respectively). Therefore, history and physical examination were the most cost-effective tools for the detection of relapse and instructing patients in nodal self-examination may be helpful.

The value of CT has not yet been evaluated in routine follow-up after treatment for HD. Khan et al. [24] compared CT and chest radiographs in the evaluation of 31 (23 HD) lymphoma patients after completion of therapy. The sensitivity of chest radiographs was only 56% of that of chest CT. Additional information provided by chest CT influenced clinical management in 33% of the cases. The higher sensitivity of CT may allow the detection of a higher number of asymptomatic relapses. In a retrospective analysis of CT in 14 patients relapsing from HD, Rahmouni et al. [25] reported radiological abnormalities detectable in six patients 2–14 months before the diagnosis of relapse. Gallium-67 scintigraphy may be a useful test to detect a recurrence even before clinical symptoms or other diagnostic tests are positive [29]. However, prospective studies are lacking to confirm the value of gallium-67 scintigraphy performed on a routine basis in the follow-up of patients after treatment.

Our study indicates that 18F-FDG PET can be positive up to 9 months before histological confirmation of an asymptomatic relapse. The compliance to undergo clinical follow-up visits was good. The median number of visits in the first and second years (when we observed all relapses) was exactly the number of visits recommended by the Cotswold Committee [26]. The compliance to undergo PET was less good with 119 studies performed out of at least 180 studies to be done. Some of the patients recruited at the end of our inclusion period have not yet finished the 3-year follow-up interval. The clinician decided to increase the interval in some patients with a better prognosis. Weihrauch et al. [20] reported a 95% disease-free survival in patients with residual mediastinal HD if the PET performed at the end of treatment was negative. Based on our data and this study we suggest an interval of 6–8 months between two PET examinations for further studies.

Unfortunately, the number of patients included in our study is insufficient to draw any definitive conclusion. The major problem with PET was the high rate of false-positivity. 18F-FDG PET incorrectly suggested a relapse in six of 11 patients (55%) with a positive PET. However, in all these cases a further PET study was negative. The reasons for these false-positive results remain unclear but atypical uptake in the thymus or digestive tract may mimic tumoral relapse. Better technical conditions (with iterative reconstruction and attenuation correction, now used routinely in our center) may possibly reduce the false-positive rate. However, four of six false-positive studies were done with iterative reconstruction and attenuation correction. Although the positive predictive value of PET is very high at the end of treatment evaluation of patients with lymphoma [30], the present study clearly indicates that histological or other evidence of disease recurrence should be obtained before the start of salvage therapy because 18F-FDG is not a tumor-specific tracer. Recent publications [19, 20] also indicate a lower positive predictive value of PET at the end of treatment evaluation of patients suffering from HD compared with previous reports [1518] that included mostly or exclusively NHL patients.

Finally, our work also gave interesting insights into physiological 18F-FDG uptake. The high number of studies showing 18F-FDG uptake related to rebound thymic hyperplasia has to be noted. False-positive CT and gallium-67 scintigraphies in areas of active thymic activity have been reported, particularly in young children [31, 32]. Increased 18F-FDG uptake in the normal thymus has also been reported in children between the ages of 2 and 13 years [33, 34]. We found thymic uptake even in 40-year-old patients. Special attention should be given to the evaluation of the anterior mediastinum even in adult patients, to avoid misinterpreting normal thymic uptake as disease recurrence in the mediastinum.

Obviously, further studies are required to evaluate fully the potential of PET in the early detection of relapse and its impact upon outcome. We have to point out that two of five patients presented palpable disease (lymph node or thyroid nodule) shortly after the first positive PET. Even if 18F-FDG PET can detect a high proportion of preclinical relapses, it will only be useful if this also influences survival by allowing an earlier start of salvage therapy. The most cost-effective schedule has also to be determined. A randomized trial of screening for cancer recurrence after curative therapy is not easily performed because of limited numbers of patients and physician and patient reluctance to experiment with follow-up procedures [27]. An alternative may be to predict the success of a screening program by evaluating its sensitivity, specificity and the duration of the preclinical interval for a given test [27]. The number of patients needed for a randomized trial evaluating the impact of PET on outcome will be unrealistic high in this chemotherapy- and radiotherapy-sensitive disease. 18F-FDG PET may be an interesting clinical research tool for future studies in patients with good prognosis. PET may not only be useful to detect incomplete remission after the induction treatment. If the patients in the less toxic experimental arm have lower first-line cure rates, the early identification of relapse during follow-up may also allow immediate start of salvage treatment.


    Acknowledgements
 
Part of the manuscript was presented at the 36th Annual Meeting of the American Society of Clinical Oncology (21 May, 2000, New Orleans, LA, USA).


    Footnotes
 
+ Correspondence to: Dr G. Jerusalem, Medical Oncology, CHU Sart Tilman, B35, B-4000 Liege 1, Belgium. Tel: +32-4-3667201; Fax: +32-4-3668855; E-mail: g.jerusalem{at}chu.ulg.ac.be Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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