British Journal of Radiology 75 (2002),S67-S73 © 2002 The British Institute of Radiology
Functional imaging for assessment of therapy
M Schwaiger
Nuklearmedizinische Klinik und Poliklinik, Klinikum r.d. Isar, Technische Universitaet Muenchen, Ismaninger Str. 22, 81675 Muenchen, Germany
 |
Introduction
|
|---|
Functional imaging signals such as the regional uptake of the radiolabelled glucose analogue fluorodeoxyglucose (FDG), which can be non-invasively defined by positron emission tomography (PET), are suitable for the assessment of the response of tumour tissue to therapeutic interventions [1]. Therefore, in addition to its documented value in diagnosing tumour tissue, FDG-PET will have a major clinical impact through its role in therapy management. This prediction is supported by the fact that relatively little health care expenditure is used for the diagnosis of cancer compared with the large financial resources directed towards therapy. Imaging methods that will reduce the cost of therapy will help to manage oncological patients cost effectively.
In addition to its promising clinical applications, PET also has an important role in clinical research. Based on the recommendations of the Director of the NCI for the fiscal budget of 2001, five particular opportunities for cancer research were identified. "Imaging of cancer" was chosen as the second most important. Closely related to this topic was "defining the signatures of cancer cells", which was also considered to be of future significance. The development of imaging signals to characterize tumour tissue and to define possible targets for therapy will emerge as an important academic challenge for the imaging community in the foreseeable future (see www.cancer.gov — budget section).
However, PET is only one of many new imaging modalities being developed. Morphological imaging with CT and magnetic resonance tomography (MR) has advanced significantly over recent years, yielding excellent temporal and spatial resolution. At the same time, new imaging approaches have been introduced to provide a variety of functional signals, which can be used for non-invasive tissue characterization. Such signals include the qualitative and quantitative assessment of tissue perfusion, metabolism and signal transmission. New targets for imaging probes will emerge as our knowledge of biology increases. The identification of specific antigen and protein expression in tumour tissue will provide new stimuli for the visualization of tumour biology in vivo [2, 3]. Finally, as gene therapy becomes a clinical reality, there is a need for methods to monitor the efficacy of transfection as well as to assess protein expression, and the role of imaging is likely to expand [4].
As we progress from structural to biological imaging, several methods are in competition (Figure 1
). The tracer approach using radioactive labelled compounds excels because of its high sensitivity. Picomolar concentrations of radiolabelled molecules can be detected in tissue, which compares favourably with MRI. However, the tracer approach is limited in specificity since radioisotopes can be separated from the labelled molecules by metabolic processes altering the regional distribution of the radioactivity. Optical imaging using fluorescence probes is most likely to compete in the future for the visualization of biological processes. However, the clinical application of this approach may be limited by the distance light can penetrate tissue [5].
The PET technology currently available produces tomographic images of the entire body, allowing visualization of regional metabolic processes with high spatial resolution (Figure 2). As a marker for glucose utilization, FDG provides high biological contrast between normal and malignant tissue. It has been known for many years that tumour tissue exhibits increased glucose uptake and glycolytic activity. This exciting new technology has gained wide clinical acceptance for diagnosing and localizing tumour tissue [6, 7]. However, its role in monitoring therapy is just now emerging. In this paper I will concentrate on the possible role of this modality to assist therapy in patients with cancer.
View larger version (61K):
[in this window]
[in a new window]
|
Figure 2. Whole body PET imaging in a patient (50 years old, male) with non-Hodgkin (MALT) lymphoma before and after chemotherapy. Multiple sites of increased FDG uptake reflecting tumour tissue are seen at the baseline. 8 weeks after therapy, only physiological distribution of FDG can be observed, identifying successful treatment.
|
|
What are the hypotheses that support the role of PET in therapy monitoring? Firstly, accurate staging of the tumour is necessary and will significantly influence the choice of therapy. Secondly, metabolic signals, such as FDG uptake, can be used to assess objectively the effect on therapy and tissue biochemistry. Several studies have shown that a decrease in metabolic activity precedes a change in tumour size [8]. Thirdly, it is necessary to identify residual tumour viability after therapy to define prognosis and to stratify the use of subsequent chemotherapy and radiotherapy. Finally, individual tissue characterization leading to the identification of therapy targets by non-invasive means may be of future importance in tailoring therapy to the needs of individual patients.
|
Pre-therapeutic staging
|
|---|
FDG-PET offers advantages for staging of tumours, because FDG accumulation in lymph nodes is independent of the size of the nodes, and therefore may be more sensitive than CT. In addition, because of the high biological contrast between tumour and non-tumour tissue this technique excels in anatomically difficult areas such as the mediastinum and the pelvis, which remain challenging for evaluation by CT. Therefore PET has been widely accepted as a diagnostic modality for the assessment of the extent of tumour tissue in patients with lung and colorectal cancer [9]. Numerous studies have been published which demonstrate the clinical utility and superiority of PET compared with staging with CT [6].
|
Detection of residual tissue viability
|
|---|
Gallium-67 scintigraphy has been used extensively to identify residual tumour tissue following chemotherapy in patients with lymphoma [10]. FDG-PET imaging offers advantages in terms of image quality as well as biological contrast (Figure 2
). It is very important to assess residual viability on completion of several courses of therapy and has been shown in many studies to be of prognostic value. Recently, Spaepen et al [11] reported on 93 non-Hodgkin lymphoma patients who underwent PET following therapy and a follow-up clinical exam at 20 months. All patients with residual FDG uptake after therapy had a relapse within the observation period, while patients with negative FDG-PET scans had a low incidence of relapse (16%). Accordingly, the relapse-free survival was 404 days significantly longer in PET-negative patients compared with 73 days in patients with a positive FDG-PET scan. Similar data were reported by Jerusalem et al [12], who showed that the negative and positive predictive values in patients with Hodgkin and non-Hodgkin lymphoma is significantly better for PET compared with CT [12]. Data from Mikhaeel et al [13] also support the observation that the relapse rate in the negative FDG-PET group is significantly lower than in a group with a positive scan. The predictive value of PET was superior to CT scanning for defining the risk of relapse. Based on the published literature, PET appears to be sensitive and specific to detect residual disease [6]. However, it has to be emphasized that the determination of the negative predictive value depends on the follow-up time. Longer observation periods are likely to reduce this value since the spatial resolution currently available for PET limits the detection of minimal residual disease. More prospective research is needed to identify the long-term prognostic value of PET imaging following chemotherapy in patients with lymphoma.
|
Therapy monitoring
|
|---|
The main focus of our research in Munich is defining the role of FDG-PET as a surrogate endpoint for monitoring therapy not only in patients with lymphoma but also in patients with solid tumours. This work is based on the following assumptions: firstly, FDG-PET can assess tumour glucose utilization with high reproducibility; secondly, the decrease in glucose utilization during therapy correlates with a reduction in viable tumour cells; and, finally, in responding tumours a reduction in glucose utilization occurs early after initiation of therapy.
Initially, we evaluated the reproducibility of FDG accumulation in malignant tumours. 16 patients undergoing phase 1 trials at our institution had repeat FDG-PET scans within the 10 day observation period prior to exposure to an experimental drug. There were no changes in anti-tumour therapy between those two scans. Various parameters (standard uptake value (SUV), Patlak slope, glucose utilization rate) derived from PET scanning were compared. In 50 lesions, there was a high reproducibility with low standard deviation. Based on these data it was concluded that changes in regional FDG uptake greater than 20% have to be considered significant in the follow-up after therapy. Analysis using the SUV, which can be easily measured, yielded similar results [14]. These results are important for the design of clinical studies, suggesting that FDG-PET is a suitable endpoint in the assessment of new therapies. Integration of PET in the development of new drugs may facilitate the pre-clinical and clinical evaluation process [15].
The second question we addressed was to evaluate if a decrease in metabolic activity after therapy correlates with a reduction in viable tumour cells. Some animal data indicated that FDG uptake increases after exposure of the cells to chemotherapy [16]. 20 patients with locally advanced oesophageal cancer who received pre-operative chemotherapy in a neo-adjuvant regimen were investigated. FDG tumour uptake prior to and following chemotherapy was compared with the results of histopathological analysis of the surgical specimen; Figure 3 depicts two examples. The first example shows a patient who responded to therapy with histological evidence of >10% tumour cells in the surgical specimen. The second example shows relatively little change in metabolic activity, identifying a non-responder. There was only minimal tumour regression based on histological analysis (Figure 3). Overall, most patients showed a decrease in metabolic activity following this specific regimen. A decrease in metabolic activity of more than 40% differentiated best between tissue samples with <10% viable tumour cells compared with samples showing evidence of residual tumour tissue [17].
View larger version (21K):
[in this window]
[in a new window]
|
Figure 3. FDG uptake in oesophageal cancer prior to and following therapy before surgical removal of the tumour. SUV decreases in the responding patient by over 70%, while SUV in the non-responder changes less than 30% [17].
|
|
|
Time course of FDG uptake after initiation of therapy
|
|---|
To define the time course of metabolic changes following therapy, patients with lymphoma were selected to serve as a model for a tumour that is likely to respond to chemotherapy. 11 patients had FDG-PET scans performed prior to chemotherapy and at days 7 and 42 after initiation. Again, various approaches to quantitate regional FDG uptake were employed. Quantitatively, about 70% of the decrease in metabolic activity occurred within the first 7 days. Only a very small change was observed between day 7 and day 42. However, the value at day 42 was more predictive for the rate of relapse and emerged as the better prognostic indicator. These data suggest that metabolic changes occur early after initiation of therapy and thus may prove useful for the identification of responders or non-responders during the early course of therapy [18].
Following these first promising results, we extended studies to patients with solid tumours. A protocol was designed to define the predictive value of FDG-PET scanning early during the time course of chemotherapy in patients with oesophageal cancer. 40 patients received pre-operative chemotherapy, and FDG-PET scanning was performed 14 days after initiation of therapy. 4 months later, all patients underwent surgery. The analysis of the data addressed the hypothesis that the scan at 14 days can predict the clinical and histological response as well as the survival. In patients who responded to neo-adjuvant therapy a clinically significant reduction in metabolic activity was seen at day 14. Receiver operating curves were used to identify the threshold of relative FDG uptake to enable the clinical and histopathological response to therapy to be predicted. A 35% reduction in regional FDG uptake correlated best with clinical response, while a 45% reduction showed the highest sensitivity or specificity to identify the histopathological response [19].
The analysis of clinical outcome in a small patient cohort is of limited use, but in these 40 patients there was a survival benefit based on the 35% reduction in regional FDG uptake [19]. These preliminary data are of potential importance for managing patients with oesophageal cancer. Neo-adjuvant therapy is applied to downstage the tumour to increase the effects of surgery. Early PET can be used to stratify these patients undergoing neo-adjuvant therapy. Responders will continue to receive therapy, while non-responders will undergo immediate surgery. A prospective study is currently being designed to determine if PET guided therapeutic management of patients with oesophageal cancer does influence clinical outcome.
Based on this research, it appears that PET is well suited to define early therapy effects. Such assessment may help tailor therapy to the needs of individual patients, which is likely to decrease side effects in patients who would not benefit from therapy and also decrease the cost of unnecessary treatment.
|
Identification of therapy targets using radiolabelled molecular probes
|
|---|
A large number of imaging tools have been developed to characterize cells, especially tumour cells. Besides assessing tissue metabolism with markers of glucose and amino acid transport, there is increased interest in antigens expressed at the surface of tumour cells, which is further supported by the emerging role of immuno/radioimmunotherapy. The quantitative nature of PET together with its high sensitivity makes this imaging modality very attractive when using radiolabelled antibodies or peptides to identify a molecular therapy target [20–23].
Pre-clinical data indicate the therapeutic potential of modifying angiogenesis in tumours. New drugs are being developed to target the angiogenetic process to inhibit tumour growth. Most of these new drugs are based on molecular targets, which can be, at least theoretically, identified by imaging techniques. In our laboratory, attempts are being made to develop imaging probes to visualize integrins [24]. A peptide directed against alpha-v beta-3 is used as imaging probe. The integrins have been shown to be associated with tumour migration and activation of endothelial cells. The chemical structure that serves as a ligand for this integrin is the RGD (Arg-Gly-Asp) peptide. The development of this imaging probe parallels the introduction of vitaxin, which also targets this integrin site. To validate this new tracer approach, animals implanted with alpha-v beta-3 positive tumours were examined using a dedicated animal PET scanner (Figure 4). Comparing tumours in the same animal with high and low expression of alpha-v beta-3 integrins, the imaging probe was highly concentrated in the positive tumours. Using a cold compound, competitive binding has been demonstrated with decreasing uptake of the radiolabelled compound [24]. Following this very promising pre-clinical study, we are currently refining the radiosynthesis to apply this technology in clinical studies.
View larger version (36K):
[in this window]
[in a new window]
|
Figure 4. Visualization of alpha-v beta-3 integrins using F-18 RGD peptide in mice implanted with alpha-V beta-3 positive and negative tumours. In addition, displacement studies with cold RGD were performed, indicating low non-specific binding of F-18 RGD [24].
|
|
The last example of monitoring therapy with molecular imaging is the use of reporter genes to identify gene expression. This method was pioneered by Blasberg's group at the Sloan Kettering Memorial Hospital and Gambhir at UCLA [4]. The most commonly pursued approach employs the herpes simplex type 1 virus thymidine kinase (HSV1-TK) gene in combination with a therapeutic gene. Herpes simplex type 1 virus thymidine kinase (HSV1-TK) is not expressed in normal mammalian cells (Figure 5). By inducing the synthesis of this enzyme, tumour cells retain the radioactive labelled thymidine analogue by phosphorylation. Animal studies have shown a close correlation between the scintigraphic signal and the expression of the messenger RNA for thymidine kinase measured in the transfected tumour [25]. Recent studies employing the same approach in humans indicate the feasibility of gene imaging using tracers [26]. However, further studies are needed to refine the method of reporter gene imaging and to address the issue of quantification. It is an important goal to develop imaging techniques to assess extent and degree of transfection efficacy quantitatively, which then can be related to the effect of gene therapy.
View larger version (33K):
[in this window]
[in a new window]
|
Figure 5. PET imaging of HSV1-TK expression in the mouse model. Following injection of J-124 FIAU (thymidine analogue), the positive HSV1-TK tumour (right side) is visible. Note the low uptake in non-transfected tissue.
|
|
In summary, as imaging expands to incorporate molecular signals, the need for interdisciplinary research increases. Cooperation among various imaging fields needs to be enhanced, since a combination of structural and functional information is necessary for image interpretation. The development of imaging fusion software and the use of combined instrumentation such as PET/CT will address this issue. Aside from software and instrumentation, the academic challenge will be to integrate the increasing knowledge in molecular biology, pharmacology, medical physics and chemistry to develop the most appropriate imaging probes. The validation of these new methods requires dedicated imaging centres that facilitate scientific exchange and the rapid transfer of new methods from the laboratory bench to the patient's bedside.
|
References
|
|---|
- Cook GJR. The clinical use of PET — where are we now? Br J Radiol 2001;74:399–401.[Free Full Text]
- Hillman BJ, Neiman HL. Translating molecular imaging research into radiologic practise: summary of the proceedings of the American College of Radiology Colloquium, April 22–24, 2001. Radiology 2002;222:19–24.[Abstract/Free Full Text]
- Schwaiger M, Wester HJ. Molecular imaging: dream or reality? Nuklearmedizin 2001;40:N19–22. (In German) [Medline]
- Gambhir SS, Herschman HR, Cherry SR, Barrio JR, Satyamurthy N, Toyokuni T, Phelps ME, Larson SM, Balatoni J, Finn R, Sadelain M, Tjuvajev J, Blasberg R. Imaging transgene expression with radionuclide imaging technologies. Neoplasia 2000;2:118–38.[Medline]
- Bremer C, Bredow S, Mahmood U, Weissleder R, Tung CH. Optical imaging of matrix metalloproteinase-2 activity in tumors: feasibility study in a mouse model. Radiology 2001;221:523–9.[Abstract/Free Full Text]
- Gambhir SS, Czernin J, Schwimmer J, Silverman DH, Coleman RE, Phelps ME. A tabulated summary of the FDG PET literature. J Nucl Med 2001;42:1S–93S.[Free Full Text]
- Reske SN, Kotzerke J. FDG-PET for clinical use. Results of the 3rd German Interdisciplinary Consensus Conference, ‘Onko PET III’, 21 July and 19 September 2000. Eur J Nucl Med 2001;28:1707–23.[Medline]
- van der Hiel B, Pauwels EK. Positron emission tomography with 2-[18F]-fluoro-2-deoxy-D-glucose in oncology: therapy response monitoring in breast cancer, lymphoma and gliomas. Cancer Res Clin Onco 2001;127:269–77.
- Prauer HW, Weber WA, Romer W, Treumann T, Ziegler SI, Schwaiger M. Controlled prospective study of positron emission tomography using the glucose analogue [18f] fluorodeoxyglucose in the evaluation of pulmonary nodules. Br J Surg 1998;85:506–11.
- Kostakoglu L, Goldsmith SJ. Positron emission tomography in lymphoma: comparison with computed tomography and gallium-67 single photon emission computed tomography. Clin Lymphoma 2000;1:67–74.[Medline]
- Spaepen K, Stroobants S, Dupont P, Van Steenweghen S, Thomas J, Vandenberghe P, Vanuytsel L, Vormans G, Balzarini J, De Wolf-Peeters C, Mortelmans L, Verhoef G. Prognostic value of positron emission tomography (PET) with fluorine-18 fluorodeoxyglucose ([18F]FDG) after firstline chemotherapy in non-Hodgkin's lymphoma; is [18F] FDG-PET a valid alternative to conventional diagnostic methods? J Clin Oncol 2001;19:414–9.[Abstract/Free Full Text]
- Jerusalem G, Beguin Y, Fassotte MF, Najjar F, Paulus P, Rigo P, Fillet G. Whole-body positron emission tomography using 18F-fluorodeoxyglucose for posttreatment evaluation in Hodgkin's disease and non-Hodgkin's lymphoma has higher diagnostic and prognostic value than classical computed tomography scanning. Blood 1999;94:429–33.[Abstract/Free Full Text]
- Mikhaeel NG, Timothy AR, O'Doherty MJ, Hain S, Maisey MN. 18-FDG-PET as a prognostic indicator in the treatment of aggressive non-Hodgkin's lymphoma - comparison with CT. Leuk Lymphoma 2000;39:543–53.[Medline]
- Weber WA, Ziegler SI, Thodtmann R, Hanauske AR, Schwaiger M. Reproducibility of metabolic measurements in malignant tumors using FDG PET. J Nucl Med 1999;40:1771–7.[Abstract/Free Full Text]
- Brady F, Luthra SK, Brown GD, Osman S, Aboagye E, Saleem A, Price PM. Radiolabelled tracers and anticancer drugs for assessment of therapeutic efficacy using PET. Curr Pharm Des 2001;7:1863–92.[Medline]
- Haberkorn U, Morr I OF, Bellemann ME, Blatter J, Altmann A, Kahn B, van Kaick G. Fluorodeoxyglucose uptake in vitro: aspects of method and effects of treatment with gemcitabine. J Nucl Med 1994;35:1842–50.[Abstract/Free Full Text]
- Brucher BL, Weber W, Bauer M, Fink U, Avril N, Stein HJ, Werner M, Zimmermann F, Siewert JR, Schwaiger M. Neoadjuvant therapy of esophageal squamous cell carcinome: response evaluation by positron emission tomography. Ann Surg 2001;233:320–1.[Medline]
- Romer W, Hanauske AR, Ziegler S, Thodtmann R, Weber W, Fuchs C, Enne W, Herz M, Nerl C, Garbrecht M, Schwaiger M. Positron emission tomography in non-Hodgkin's lymphoma: assessment of chemotherapy with fluorodeoxyglucose. Blood 1998;91:4464–71.[Abstract/Free Full Text]
- Weber WA, Ott K, Becker K, Dittler HJ, Helmberger H, Avril NE, Meisetschlager G, Busch R, Siewert JR, Schwaiger M, Fink U. Prediction of response to preoperative chemotherapy in adenocarcinomas of the esophagogastric junction by metabolic imaging. J Clin Oncol 2001;19:3058–65.[Abstract/Free Full Text]
- Boerman OC, Oyen WJ, Corstens FH. Radio-labeled receptor-binding peptides: a new class of radiopharmaceuticals. Semin Nucl Med 2000;30:195–208.[Medline]
- Stocklin G, Wester HJ. Positron emission tomography: a critical asessment of recent trends. In: Gulyás B, Müller-Gärtner HW (editors). Strategies for radioligand development: peptides for tumor targeting. The Netherlands: Kluwer Academic Publishers. 1998:57–90.
- Okarvi SM. Recent progress in fluorine-18 labelled peptide radiopharmaceuticals. Eur J Nucl Med 2001;28:929–38.[Medline]
- Schumacher J, Kaul S, Klivenyi G, Junkermann H, Magener A, Henze M, Doll J, Haberkorn U, Amelung F, Bastert G. Immunoscintigraphy with positron emission tomography: gallium-68 chelate imaging of breast cancer pretargeted with bispecific anti-MUC1/anti-Ga chelate antibodies. Cancer Res 2001;61:3712–7.[Abstract/Free Full Text]
- Haubner R, Wester HJ, Weber WA, Mang C, Ziegler SI, Goodman SL, Senekowitsch-Schmidtke R, Kessler H, Schwaiger M. Noninvasive imaging of alpha(v)beta3 integrin expression using 18F-labeled RGD-containing glycopeptide and positron emission tomography. Cancer Res 2001;61:1781–5.[Abstract/Free Full Text]
- Tjuvajev JG, Chen SH, Joshi A, Joshi R, Guo ZS, Balatoni J, Ballon D, Koutcher J, Finn R, Woo SL, Blasberg RG. Imaging adenoviral-mediated herpes virus thymidine kinase gene transfer and expression in vivo. Cancer Res 1999;59:5186–93.[Abstract/Free Full Text]
- Jacobs A, Voges J, Reszka R, Lercher M, Gossmann A, Kracht L, Kaestle C, Wagner R, Wienhard K, Heiss WD. Positron-emission tomography of vector-mediated gene expression in gene therapy for gliomas. Lancet 2001;358:727–9.[Medline]
Top
Introduction
Pre-therapeutic staging
