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Journal of Clinical Oncology, Vol 22, No 6 (March 15), 2004: pp. 1034-1039 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.07.188 2-18fluoro-deoxy-D-glucose Positron Emission Tomography Is a Reliable Predictor for Viable Tumor in Postchemotherapy Seminoma: An Update of the Prospective Multicentric SEMPET TrialFrom the Departments of Medical Oncology, Surgery and Ludwig Boltzmann Institute for Applied Cancer Research, Kaiser Franz Josef Spital; Department of Nuclear Medicine, University of Vienna Medical School, Vienna; Austrian Study Group on Urologic Oncology, Landeskrankenhaus Feldkirch, Austria; and the Department of Medical Oncology and Institute of Nuclear Medicine, University of Tübingen, Tübingen, Germany. Address reprint requests to Jörg Pont, MD, 3 Medizinische Abteilung mit Onkologie, Kaiser Franz Josef Spital, Kundratstrasse 3, A-1100 Wien, Austria; e-mail: joerg.pont{at}univie.ac.at
PURPOSE: To define the clinical value of 2-18fluoro-deoxy-D-glucose positron emission tomography (FDG PET) as a predictor for viable residual tumor in postchemotherapy seminoma residuals in a prospective multicentric trial.
PATIENTS AND METHODS: FDG PET studies in patients with metastatic pure seminoma who had radiographically defined postchemotherapy residual masses were correlated with either the histology of the resected lesion or the clinical outcome documented by computer tomography (CT), tumor markers, and/or physical examination during follow-up. The size of the residual lesions on CT, either > 3 cm or
RESULTS: Fifty-six FDG PET scans of 51 patients were assessable. All 19 cases with residual lesions > 3 cm and 35 (95%) of 37 with residual lesions CONCLUSION: This investigation confirms that FDG PET is the best predictor of viable residual tumor in postchemotherapy seminoma residuals and should be used as a standard tool for clinical decision making in this patient group.
Of all pure seminoma patients, approximately 25% present with advanced clinical stage disease [1,2]. After adequate cisplatin-containing chemotherapy, which usually consists of four courses of cisplatin and etoposide or three courses of etoposide and cisplatin plus bleomycin, approximately 56% to 78% of these patients are found to have radiologically detectable masses after chemotherapy [3-8]. The management of postchemotherapy seminoma residuals is still controversial. There are several options in clinical practice: some centers recommend surgery for lesions > 3 cm [4,5,9], although surgery is technically demanding in these patients as a result of fibrosis and desmoplastic reactions [10-12]. A number of patients with poorly defined residual lesions are rated as inoperable. Attempted resections of these lesions are often incomplete [13,14]. Therefore, some centers recommended an expectatory approach to residual lesions. These centers use salvage treatment only for documented relapses or if the residual masses fail to shrink [6,10]. In some centers, radiotherapy for residual lesions is still used, even though its role has diminished, as it was not shown to contribute to a significantly better survival rate [8]. The rationale for the present investigation is based on the hypothesis that 2-18fluoro-deoxy-D-glucose positron emission tomograhy (FDG-PET) might discriminate viable tumor from necrosis/fibrosis in residuals of pure seminoma and thus may be helpful in clinical decision making by detecting viable tumor noninvasively. FDG PET is known to provide this information with high predictive impact in several other malignancies [15-18]. Our trial started in 1997 and was designed to test this hypothesis. So far, two reports with limited patient numbers were published [19,20], one of them by us. Their results were conflicting. Possible reasons for the discrepancy in outcome were discussed in detail elsewhere [20]. This prompted us to continue our trial and extend both the follow-up and the number of patients for a larger-sized analysis. The trial outline, inclusion and exclusion criteria, and FDG PET method were published earlier together with an analysis of the first 37 cases [20].
Patients Inclusion criteria. Patients with metastases of pure testicular or extragonadal seminomas who had negative tumor markers (beta-human chorionic gonadotropin and lactate dehydrogenase) on completion of platinum-containing first-line or salvage chemotherapy and who showed clearly defined and measurable residual masses of at least 1 cm in diameter on computed tomography (CT) were eligible for our study. Exclusion criteria. Patients with nonseminomatous elements in the primary tumor and/or elevated serum alpha-fetoprotein levels at the time of diagnosis or at any subsequent point in time were excluded from this study, as were patients without clearly defined and measurable residual lesions after chemotherapy or with residual masses less than 1 cm in diameter. Patients who had completed or were scheduled for postchemotherapy radiotherapy at the site of the residual lesion of interest were also not eligible for the study. Patients were informed that the PET study proposed to them was not yet an established standard diagnostic tool for residual seminomatous lesions and was being offered to them in the context of a clinical trial. The Ethics Committee of the trial coordinating center at our institution, the Kaiser Franz Josef Spital (Vienna, Austria), felt that formal approval was unnecessary, because FDG PET was a recognized diagnostic imaging technique for other tumor entities. The study was also approved by the Tuebingen University Ethics Committee.
Methods CT scans were read by the radiologists of the participating centers according to standard care. In one case of doubtful consistency and plausibility, the CT scans were reviewed by the reference radiologist of the coordinating center.
The transverse diameter of all residual lesions was measured and the largest diameter was recorded. Only well defined masses FDG PET scans were obtained with a dedicated PET system (GE Advance, General Electric, Milwaukee, WI) covering an axial field-of-view of 15.2 cm. At the centers, the system had an axial resolution of 4 mm and a transaxial resolution of 3.8 mm [24]. One patient was scanned with a rotating partial ring system (ECAT ART, Siemens/CTI, Knoxville, TN) with an axial field-of-view of 16.2 cm and maximal axial and transaxial resolutions of 6 mm [25]. After a fast for at least 4 hours, patients were injected 370 MBq (10 mCi) of FDG intravenously. Blood glucose levels were determined and found to be within normal limits throughout. Scans from the chin to the thighs and of the brain, if indicated, were recorded after an uptake time of at least 45 minutes. Attenuation-corrected scan data were reconstructed by filtered backprojection and iterative algorithms and reformatted in coronal and transaxial slices. The scans were interpreted visually. Interpretation criteria included localization, shape, and intensity of the increased uptake. Scans were classified as negative or positive for malignancy. The standardized uptake values of positive lesions from attenuation-corrected scans were recorded. The postchemotherapy management of the residual lesions consisted in either surgery or surveillance. The choice depended on the usual policy of the contributing centers. The type of surgery performed and the extent of resection (complete or incomplete) was recorded. Follow-up studies were scheduled at 3-month intervals in the first 2 years and at 6-month intervals thereafter. PET scan results (positive or negative) were correlated with the histology of the resected lesion (presence or absence of viable residual tumor tissue) or the radiologic and clinical course (presence or absence of progressive disease). Positive PET scans of residual lesions were rated true-positive when either viable tumor was found to be present histologically, or clinical progression and/or progression on CT was seen. If there was neither viable tumor histologically, nor clinical progression nor progression on CT, positive PET scans were rated false-positive. Negative PET scans with necrosis or fibrosis in the resected residual lesion or absence of clinical disease as defined above were rated true-negative. Negative PET scans with viable tumor in the resected residual lesion or progression on CT and/or clinical progression were rated false-negative.
Of the 53 patients enrolled, two were excluded from the analyses, one because of early death as a result of bleomycin pneumonitis, and one because of irradiation of the residual lesion in violation of the trial protocol. All 56 PET scans of 51 patients from six centers in Austria and one center in Germany were assessable in June 2003. Four centers contributed 20, 16, eight, and four patients, respectively. Three centers contributed one patient each. Four patients underwent multiple PET studies in the course of their disease; one patient after first-, second - and third-line chemotherapy and three patients after first- and second-line chemotherapy. The first batch of data (37 PET scans of postchemotherapy residual masses in 33 patients and their characteristics) were reported elsewhere [20]. The patient characteristics are listed in Table 1.
The median follow-up period counted from the date of the PET scan was 34 months (range, 2 to 71 months) in June 2003. The median chemotherapy-PET scan interval was 42 days.
Eleven residual lesions were resected. Seven of them were > 3 cm and four were Forty-five cases were followed clinically. Altogether, 37 lesions showed clear shrinkage, first documented after a median follow-up time of 5 months (range, 2 to 20 months). Of these, 26 disappeared after a median follow-up of 18 months (range, 3 to 40 months). In one case, the size of the lesion was stable longer than 24 months. In the case of the largest single residual lesion of 11 cm, the size of the primary prechemotherapy mass was 20 cm. This lesion shrunk during treatment and was negative on PET scanning 38 days after the end of chemotherapy. The contributing center considered surgery to be too risky for the patient and most likely incomplete, and opted instead for surveillance by CT scanning, tumor marker assays, and clinical follow-up. Continued, albeit very slow, shrinkage of the single 11-cm lesion was first noted 4 months after the end of chemotherapy. There has been no relapse in the past 2 years. Seven of 19 lesions > 3 cm contained viable tumor confirmed by histology in three cases and by follow-up in four cases. In four resected lesions > 3 cm, only fibrosis was found to be present in the histological specimen. Eight lesions > 3 cm were followed clinically without any sign of relapse as defined in the protocol.
In three of 37 cases with residual lesions
All of the eight lesions with positive PET scans (Table 2) contained viable residual tumor confirmed by histology in three and by follow-up in five instances. Of the 48 negative PET scans, only two were false negative, both with lesions  3 cm (Table 3). In both patients, mediastinal and supraclavicular relapses occurred after 4 and 5 months, respectively.
The specificity, sensitivity, positive predictive value, and negative predictive value of FDG PET were 100% (95% CI, 92% to 100%), 80% (95% CI, 44% to 95%), 100% (95% CI, 63% to 100%) and 96% (95% CI, 85% to 99%), respectively, versus 74% (95% CI, 58% to 85%), 70% (95% CI, 34% to 90%), 37% (95% CI, 16% to 69%) and 92% (95% CI, 78% to 98%), respectively, for CT discrimination of the residual tumor by size (>/ 3 cm; Table 4).
In summary, all 19 lesions > 3 cm (100%) and 35 of 37 (95%) lesions 3 cm were correctly predicted by FDG PET.
The management of postchemotherapy residual masses in pure seminoma patients is a matter of controversy. Retrospective analyses showed a diminishing role of radiotherapy in residual lesions after chemotherapy for metastatic seminoma [6,8]. Therefore, the two main options are surgery or surveillance. Radiotherapy should be reserved for the rare cases with incomplete resection of viable residual tumor.
The importance of the size of residual lesions for the likelihood of residual viable tumor is well documented in the literature. With a cutoff of
On the other hand, the frequently cited paper of Friedman et al [11], which defined postchemotherapy surgery in seminoma patients in terms of high morbidity and mortality, is based on only three patients who underwent residual tumor resection, two of which died of postoperative complications (adult respiratory distress syndrome and septicemia). In other studies [5,13,28], the surgical problems were reported to be minor. Ravi et al [13] and Logothetis et al [29] found that poorly defined residuals, even those The clinical phenomenon of lesion shrinkage, which is used for clinical decision making in some centers, varied widely in our series, with first signs of shrinkage at a median follow-up time of 5 months (range, 2 to 20 months). Of the patients in our study, there was only one without evidence of shrinkage during follow-up. He has been disease-free for more than 24 months. In 74% of the patients on follow-up, spontaneous resolution of residuals occurred after 3 to 40 months. Our data thus suggest that lesion shrinkage is not a reliable, clinically relevant variable. If all patients with residual lesions were subjected to surveillance, up to 55% (27% to 55%) of them with lesions > 3 cm would have residual viable tumor and would therefore be at risk of relapsing [4,5,9,13]. Retrospective data indicate that the long-term disease-free survival of pure seminoma patients with recurrent or progressive disease is no better than 39% to 48% [5,14,30,31].
The current two controversial recommendations for the management of postchemotherapy seminoma residuals (ie, surgery for well defined residuals
Of more than 200 patients in the nine prospective studies on residual postchemotherapy lesions, 58 underwent surgery and 147 were kept on surveillance. Four of 48 patients (8%) relapsed after surgery. No patient (zero of 35) undergoing resection of their residual tumor died of the primary disease. Of the patients on surveillance, 16% (22 of 140) relapsed. In 15 patients (83%) of this group, the relapse occurred at the site of the residual lesion, and elsewhere in two of 14 patients (14%). Of the surveillance group, 6% (eight of 132) died of the underlying disease or of causes related to salvage treatment. 10% (four of 41) of them were on surveillance for seminoma residuals  3 cm (Tables 5 and 6).
Fully aware of the limitations of such an analysis, we still consider surgery to be the treatment of choice for residuals with a high likelihood of viable tumor. In-site relapses after complete resections are rare and the overall outcome in patients undergoing surgery appears to be favorable. FDG PET is a new addition to the battery of tools available for identifying patients at high risk of relapsing. While CT evaluates the number and size of residuals and the chances of complete resections, FDG PET provides information on tumor viability. Combined with CT scans, FDG PET helps to define the best treatment approach to the individual patient and to avoid overtreatment. Whether to use surgery alone, conventional-dose or high-dose salvage chemotherapy in patients with viable residual tumor has so far not been studied prospectively and needs further investigations. In conclusion, our results confirm that FDG PET reliably predicts viable tumor in postchemotherapy seminoma residuals. We consider FDG PET performed within the correct timeframe (4 to 12 weeks after chemotherapy) to be a new standard diagnostic tool for clinical decision-making in seminoma patients with postchemotherapy residual masses. The main advantage of using FDG PET is that in patients with residual lesions > 3 cm, surgery can be omitted safely, if PET scans are negative. PET-positive residual lesions must be regarded as harboring viable tumor and should be resected, if technically possible.
The authors indicated no potential conflicts of interest.
We recognize the contributions of Saskia Pfefferkorn, Landeskrankenhaus Feldkirch; Klaus Jeschke and Peter Lind, Landeskrankenhaus Klagenfurt; Georg Hopfinger, Hanuschkrankenhaus, Vienna; and Karl Scheibner, Hall in Tyrol, Austria. We are indebted to Günter Strau, Kaiser Franz Josef Spital, Vienna, Austria, for his radiological expertise.
These data were presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago IL, May 31-June 3, 2003, and at the 50th Annual Meeting of the Society of Nuclear Medicine, New Orleans, LA, June 21-25, 2003. Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
