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¹⁸Fluorodeoxyglucose Positron Emission Tomography in the Prediction of Relapse in Patients With High-Risk, Clinical Stage I Nonseminomatous Germ Cell Tumors: Preliminary Report of MRC Trial TE22—The NCRI Testis Tumour Clinical Study Group

Robert A. Huddart, Michael J. O'Doherty, Anwar Padhani, Gordon J.S. Rustin, Graham M. Mead, Johnathan K. Joffe, Paul Vasey, Stephen J. Harland, John Logue, Gedske Daugaard, Sharon F. Hain, Sarah J. Kirk, Jane E. MacKewn, Sally P. Stenning

From the Academic Radiotherapy, Institute of Cancer Research and Royal Marsden Hospital, Surrey; Department of Nuclear Medicine, St Thomas' Hospital; Medical Research Council Clinical Trials Unit; Middlesex Hospital, London; Paul Strickland Scanner Centre, Mt Vernon Hospital, Middlesex; Southampton General Hospital, Southampton; St James' University Hospital, Leeds; Beatson Oncology Centre, Glasgow; Christie Hospital, Manchester, UK; Rigshospitalet, Copenhagen, Denmark

Address reprint requests to Robert Huddart, PhD, Academic Radiotherapy, Institute of Cancer Research and Royal Marsden Hospital, Downs Rd, Sutton, Surrey, SM2 5PT UK; e-mail: Robert.Huddart{at}icr.ac.uk

	ABSTRACT

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Purpose There are several management options for patients with clinical stage I (CS1) nonseminomatous germ cell tumors (NSGCT); this study examined whether an ¹⁸fluorodeoxyglucose positron emission tomography (¹⁸FDG PET) scan could identify patients without occult metastatic disease for whom surveillance is an attractive option.

Methods High-risk (lymphovascular invasion positive) patients with CS1 NSGCT underwent ¹⁸FDG PET scanning within 8 weeks of orchidectomy or marker normalization. PET-positive patients went off study; PET-negative patients were observed on a surveillance program. The primary outcome measure was the 2-year relapse-free rate (RFR) in patients with a negative PET scan (the negative predictive value). Assuming an RFR of 90% to exclude an RFR less than 80% with approximately 90% power, 100 PET-negative patients were required; 135 scanned patients were anticipated.

Results Patients were registered between May 2002 and January 2005, when the trial was stopped by the independent data monitoring committee due to an unacceptably high relapse rate in the PET-negative patients. Of 116 registered patients, 111 underwent PET scans, and 88 (79%) were PET-negative (61% of preorchidectomy marker–negative patients v 88% of marker-positive patients; P = .002); 87 proceeded to surveillance, and one requested adjuvant chemotherapy. With a median follow-up of 12 months, 33 of 87 patients on surveillance relapsed (1-year RFR, 63%; 90% CI, 54% to 72%).

Conclusion Though PET identified some patients with disease not detected by computed tomography scan, the relapse rate among PET negative patients remains high. The results show that ¹⁸FDG PET scanning is not sufficiently sensitive to identify patients at low risk of relapse in this setting.

	INTRODUCTION

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Approximately 65% of all patients presenting with nonseminomatous germ cell tumors (NSGCT) will have no evidence of disease beyond the testis (stage I disease). Despite these findings, up to 30% of these patients and 35% to 50% of pathologically defined high-risk patients will experience relapse.¹ Treatment options for these patients include the use of initial surveillance with treatment at relapse, adjuvant chemotherapy and retroperitoneal lymph node dissections (± adjuvant chemotherapy). Each approach achieves similarly high cure rates (> 98%).

Surveillance is an attractive option as treatment with its associated short- and long-term morbidity risks can be avoided in patients who remain disease-free. Surveillance would be even more attractive if a greater proportion of patients with occult metastatic disease (destined to relapse at some point) could be identified earlier. These patients could be administered earlier potentially less-toxic treatment, while the overall risk of relapse in those with no identifiable disease would be lower.

NSGCT avidly take up fluorodeoxyglucose (FDG) and a number of studies have shown that ¹⁸FDG positron emission tomography (PET) imaging can demonstrate disease extent more precisely than standard cross-sectional imaging.^2-12

A Danish pilot study in stage I NSGCT showed that ¹⁸FDG PET could identify 70% of patients who subsequently relapsed with metastatic NSGCT.¹³ Similar results were obtained in a small German study comparing ¹⁸FDG PET and retroperitoneal lymph node dissection.¹⁴ The negative predictive value of the Danish study was 92%, which, if confirmed, would suggest that adjuvant treatment could be avoided in most patients with stage I NSGCT and a negative PET. To confirm these data, we have undertaken a multicenter study of this approach. In this study, patients with stage I NSGCT and high-risk features defined by vascular (lymphatic or venous) invasion underwent an ¹⁸FDG PET scan. Patients with positive scans were generally offered chemotherapy, while patients with negative scans underwent surveillance. This study was closed on recommendation of the independent data monitoring committee (IDMC) in January 2005, and this report represents our preliminary results.

	METHODS

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The trial protocol was reviewed and approved by a central research ethics committee, and all participating centers obtained local ethics committee approval to participate in the trial.

Eligibility
Eligible patients had histologically proven nonseminomatous or mixed seminoma/NSGCT with evidence of vascular (lymphatic or venous) invasion (pT2) in the primary specimen. They had clinical stage I disease on the basis of clinical examination, chest x-ray and computed tomography (CT) scan (of the chest, abdomen, and pelvis) and negative postorchidectomy tumor markers (alpha fetoprotein [AFP], and the beta subunit of human chorionic gonadotrophin [ßHCG]). The definition of stage I disease was based on a review by Carrington¹⁵; the criteria for lymph node size are detailed in Table 1. Accordingly, for abdominal nodes from the celiac axis to the renal artery, a cutoff of 10 mm was used, and from the renal artery to aortic bifurcation, a 12-mm cutoff was used. Patients with evidence of active inflammatory or infective diseases, and those who had had a previous PET scan were excluded.

PET Scanning Procedures
All studies were performed on full-ring PET and PET-CT cameras. To ensure standardization of acquisition protocols and image quality across the various centers and scanner models, all PET centers taking part in the trial underwent a quality control assessment before accreditation. The assessment included scanning of an image quality phantom, establishment of image reconstruction parameters, assessment of local quality control procedures, and establishment of protocols for secure data transfer to the central reporting site.¹⁶ Before the scan, patients were asked to fast for 6 hours and were then administered 350 to 400 MBq ¹⁸FDG. A non–attenuation-corrected "half-body" scan was performed, covering the area from the base of the brain to midthigh. The emission scan was scheduled to start 1 hour after injection and was followed immediately by an attenuation-corrected local view over an approximately 20-cm field of view from the celiac lymph nodes to the iliac lymph node chain. Any deviations from the standard protocol were recorded. All images were reconstructed using the ordered subset expectation maximization algorithm. Four centers had PET-CT scanners (during the course of the study), but the PET-only scans were reported to ensure no additional information was obtained from the CT scan component. Each scanner had the same quality assurance procedure.

All PET scans were centrally reviewed and reported by radiologists (M.J.O.'D. and S.H.) blinded to the patient's outcome. A PET scan was deemed positive if there was increased ¹⁸FDG uptake above the normal surrounding tissue in an area where metastases could be found.

Management
Patients with a positive scan went off study, and were treated according to local practice with the expectation they would receive adjuvant BEP (bleomycin, etoposide, cisplatin) chemotherapy. Patients with negative PET scans proceeded to surveillance.

All patients on surveillance were required to attend follow-up assessments at monthly intervals for the first year, every 2 months for the second year, every 3 months for the third year, and every 4 to 6 months in subsequent years. At each visit, in addition to clinical examination and chest x-ray, blood was taken for measurement of AFP, ßHCG, and lactate dehydrogenase (LDH). Abdominal and chest CTs were undertaken according to the centers' usual practice, providing this entailed scans at 3 and 12 months, or more frequently. Alternatively, patients could be randomly assigned into the ongoing Medical Research Council (MRC) TE08 randomized trial of two versus five CT scan schedules (abdominal and chest CT scans at either 3 and 12 months, or 3, 6, 9, 12, and 24 months from orchidectomy).

Statistical Considerations
The primary outcome measure of the study was relapse in PET scan–negative patients. The 2-year relapse-free rate defined the negative predictive value (NPV) of a PET scan.

The pilot study¹³ suggested that ¹⁸FDG PET may have a sensitivity of 70% and a specificity of 100%. The NPV was 92%, but this was based on only 39 scan-negative patients. This study aimed to estimate the NPV with much greater accuracy in order to determine whether it lies within a clinically useful range. Assuming an NPV of 90%, we wished to exclude a negative predictive value of less than 80% (if PET was of no benefit in identifying patients at risk of relapse, the expected relapse-free rate in this group would be approximately 65%). This would require 100 PET-negative patients to be assessed for approximately 90% power at the 5% (one-sided) significance level.¹⁷ Assuming a 35% relapse rate at 2 years among high-risk patients, and 70% sensitivity for PET scanning, this implied a total sample size of approximately 135 patients to be observed and to have scans performed.

An IDMC was established for the trial and met on three occasions (November 2002, 17 patients reviewed; December 2003, 48 patients reviewed; and January 2005, 108 patients reviewed) to review accrual, compliance, and outcome data. At their last meeting, the IDMC recommended early closure of the trial, and this was endorsed by the independent trial steering committee.

Relapse rates were calculated using the Kaplan-Meier method, and the NPV (2-year relapse-free rate) was estimated with 90% CIs to reflect the design parameters. Categorical data were compared using the ² test.

	RESULTS

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Patient Characteristics
A total of 116 patients were registered onto this study. One patient was ineligible (markers had not normalized), three patients were not present for a PET scan (two withdrew consent, one declined after IDMC recommendation of trial closure), and one patient received a scan at a nonaccredited center. Therefore, 111 patients underwent scans at accredited centers and form the main study group. Patient characteristics are presented in Table 2. The mean age of patients was 30.4 years. Fifty-five (49.5%) patients had malignant teratoma undifferentiated (MTU; embryonal carcinoma), and most of the remainder (41 patients, 36.9%) had malignant teratoma intermediate (mixed embryonal carcinoma and teratoma). Sixty-six (59.4%) patients had one or more raised markers preorchidectomy (AFP, 57 patients; 51.4%; ßHCG, 51 patients, 45.9%)

Outcome of PET-Negative Patients
Of the 88 PET-negative patients, one requested adjuvant chemotherapy while 87 underwent surveillance. With a median follow-up time from orchidectomy of 12 months, 33 patients have relapsed. In these 33 patients, the median time to relapse from orchidectomy was 6 months. The 1-year relapse free survival rate was 63.3% (90% CI, 53.5% to 71.6%; Fig 1). Including the PET-positive patients as "relapsed" at time zero, the overall 1-year relapse-free survival rate of the cohort is 50.1% (90% CI, 41.6% to 58.0%; Fig 2).

View larger version (11K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Relapse-free rates (RFRs) in positron emission tomography–negative patients. (*) The 2-year relapse-free rate was 56.1% (90% CI, 45.8% to 65.3%).

View larger version (11K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Relapse-free rates (RFRs) in all patients, assuming positron emission tomography–positive to have relapsed at outset.

With a median follow-up of 14 months from trial entry, one PET-positive patient relapsed 5 months after having received two courses of adjuvant BEP and at the time of publication is being assessed for further treatment. One patient treated with BEP who died from chronic liver disease considered to have been exacerbated by chemotherapy.

	DISCUSSION

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This study was designed on the basis that the estimated 2-year relapse-free rate should be approximately 90% and wished to exclude a rate of 80% or less. This target was achievable given 70% sensitivity reported in previous studies. The patient outcome details were reviewed by the IDMC when 118 of the target 135 patients had been recruited, and PET scan results were known for 96 patients. At that time 23 of 78 PET-negative patients had relapsed with an estimated 1-year relapse free rate of 65% (90% CI, 53% to 74%). With no further relapses it was estimated that the best achievable 2-year relapse-free rate was 70% (90% CI, 60% to 79%), which was still below the minimum rate accepted as showing the approach to be successful. On this basis, it was recommended that study recruitment be suspended.

In this study, we were unable to reproduce the results of previously published studies. We cannot be certain as to the reasons for this discrepancy. The patient characteristics and staging of the main pilot study of Lassen et al¹³ were similar to this protocol. The results of Lassen et al were based on PET detecting seven of 10 patients with relapse. CT review did show that two of these patients had 1-cm lymph nodes at study entry and a further patient had uptake in the groin and relapsed at a different site. If these patients were excluded, then the results of Lassen et al would be similar to those reported here.

Unlike the study of Lassen et al,¹³ this was a multicenter study with scans undertaken at a variety of PET centers. However, all scanning was undertaken at modern, commercial, whole-body PET or PET/CT facilities, and a process of quality assurance was instituted. Minimum scanning sensitivity was mandated and checked by phantom measurements (J.M., M.J.O.'D.) and all PET scans were reported centrally by two observers (M.J.O.'D., S.H.).

In contrast to Lassen et al, we selected high-risk (vascular invasion–positive) patients for this study. As the NPV in this case is dependent on the expected relapse rate, it is important to consider whether the patients entered onto the trial represented a group at substantially higher risk of relapse than that anticipated. The expected relapse rate in unselected high-risk patients of 35% is based on long-term follow-up of the MRC prospective surveillance study.¹ This is similar to early results from high-risk patients in the MRC TE08 trial¹⁸ of two CT scan schedules in surveillance of stage I nonseminoma patients, which reported a 2-year relapse-free rate of 33.4% in high-risk patients. In this study, the proportion of patients with relapse or positive PET scan was higher than anticipated at approximately 50% at 1 year. We have no reason to believe that factors other than vascular invasion were used to identify high-risk patients in this study, and this rate is in line with other published experience on high-risk NSGCT. Whether inclusion of patients with suspicious lymph nodes has increased this rate is being examined in a more detailed central imaging review.

Despite this difference in relapse risk, our 90% CIs for the 1-year relapse-free rate exclude rates above 71%. We therefore believe these results to suggest that PET scanning as undertaken in this study is not sufficiently sensitive to detect micrometastases.

¹⁸FDG PET did identify the presence of disease in a proportion of patients (approximately 21%). The chance of PET being positive was associated with both the preoperative marker status and primary histology (Table 2). This would suggest that when markers are not raised, ¹⁸FDG PET may be of greater value at detecting disease sites. This phenomenon was reported in the surveillance studies in the 1980s in which absence of yolk sac elements was suggested as a risk factor for relapse.¹⁹ Despite this, a substantial risk of relapse remains in patients following a negative PET scan.

How should we respond to these results? We cannot recommend that a single ¹⁸FDG PET scan as used in this study replace current strategies for managing high-risk stage I NSGCT patients, though PET could help detect relapse earlier in some patients. It may also be questioned whether a single PET scan after diagnosis, as used in this study, is the most effective way of utilizing functional imaging. A previous UK retrospective study suggested that ¹⁸FDG PET can detect relapse before morphologic changes and showed more sites of disease than CT alone when used as an initial staging tool.^20,21 The question is whether surveillance with ¹⁸FDG PET, or now more likely PET CT, would be more appropriate and sensitive than follow-up with morphologic imaging alone especially as recent studies have shown that two CTs provide sufficient cross-sectional imaging in NSGCT surveillance programs.¹⁸ These questions would need a further study, which would need to address whether functional imaging offers real health benefits.

We conclude that though ¹⁸FDG PET identified a proportion of patients with presumed disease not detected by CT scan, the relapse rate among PET negative patients remains high. The study results therefore suggest that ¹⁸FDG PET scanning is not able to identify patients at sufficiently low-risk of relapse to guide management decisions in this setting.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

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Conception and design: Robert A. Huddart, Michael J. O'Doherty, Anwar Padhani, Sally P. Stenning

Administrative support: Sarah J. Kirk, Sally P. Stenning

Provision of study materials or patients: Robert A. Huddart, Gordon J.S. Rustin, Graham M. Mead, Johnathan K. Joffe, Paul Vasey, Stephen J. Harland, John Logue, Gedske Daugaard

Collection and assembly of data: Sarah J. Kirk, Jane E. MacKewn, Sally P. Stenning

Data analysis and interpretation: Robert A. Huddart, Michael J. O'Doherty, Anwar Padhani, Sarah J. Kirk, Sally P. Stenning

Manuscript writing: Robert A. Huddart, Michael J. O'Doherty, Anwar Padhani, Gordon J.S. Rustin, Graham M. Mead, Johnathan K. Joffe, Paul Vasey, Stephen J. Harland, John Logue, Gedske Daugaard, Sharon F. Hain, Sarah J. Kirk, Sally P. Stenning

Final approval of manuscript: Robert A. Huddart, Michael J. O'Doherty, Anwar Padhani, Gordon J.S. Rustin, Graham M. Mead, Johnathan K. Joffe, Paul Vasey, Stephen J. Harland, John Logue, Gedske Daugaard, Sharon F. Hain, Sarah J. Kirk, Jane E. MacKewn, Sally P. Stenning

Other: Michael J. O'Doherty [Trial management group member, coordinator of positron emission tomography (PET) scan center accreditation, central review of PET scans], Anwar Padhani [Trial management group member, coordinator of computed tomograhy scan review study], Sharon F. Hain [Involved in the accrediation of positron emission tomography (PET) scan centers, central review and reporting to PET scans], Jane E. MacKewn [Involved in the accreditation of positron emission tomography (PET) scan centers and transfer of data for central review]

	ACKNOWLEDGMENTS

 
This study was initiated by the chief investigator, Dr Huddart, on behalf of the National Cancer Research Institute Testis Cancer Clinical Studies Group, designed, conducted and analyzed in collaboration with the MRC Clinical Trials Unit (statisticians S. Stenning and S. Kirk; Trial manager L. McDonald; Data Manager P. Pollock), and funded by Cancer Research UK. Dr O'Doherty and Dr Hain undertook central review of the PET scans, and Dr Padhani undertook central review of CT scans. The Independent Data Monitoring Committee (Chair: Judith Bliss, Institute of cancer research, Sutton; Hans-Joachim Schmoll, Universität Halle-Wittenburg; Graham Read, Royal Preston Hospital) and the Trial Steering Committee (Chair: Dr David Guthrie, Derby; Dr Helena Earl, Cambridge; Professor Colin McArdle, Glasgow) provided independent oversight of the trial. We thank staff and patients at all the participating hospitals and PET centers:

Participating Hospitals

Royal Marsden Hospital, Sutton: 14 patients (Dr R Huddart, Dr D Dearnaley, Prof A Horwich)

Mount Vernon Hospital, Middlesex: 11 patients (Professor G Rustin)

Southampton General Hospital, Southampton: 9 patients (Dr GM Mead, Dr P Simmonds)

St James University Hospital, Leeds: 9 patients (Prof P Selby, Dr J Joffe, Dr JD Chester)

Beatson Oncology Centre, Glasgow: 8 patients (Dr P Vasey, Dr J White)

Christie Hospital, Manchester: 8 patients (Dr J Logue)

Middlesex Hospital: 8 patients (Dr S Harland)

Bristol Oncology Centre, Bristol: 6 patients (Dr J Graham, Dr J Braybrooke)

Rigshospitalet, Copenhagen, Denmark: 6 patients (Dr G Daugaard)

Addenbrooke's hospital, Cambridge: 4 patients (Dr MV Williams)

Belfast City Hospital: 4 patients (Dr JJ McAleer)

Southend General Hospital: 4 patients (Dr P Leonard, Dr O Koriech)

Northern Centre for Cancer Treatment, Newcastle: 3 patients (Dr JT Roberts, Dr R McMenemin)

Royal Sussex County hospital, Brighton: 3 patients (Dr D Bloomfield)

St Bart's hospital, London 3 patients (Professor RTD Oliver)

Aberdeen Royal Infirmary, Aberdeen: 2 patients (Dr D Bissett)

Nottingham City Hospital, Nottingham: 2 patients (Dr M Sokal)

Royal Berkshire 2 patients: (Dr P Rogers, Dr Brown)

Royal Devon & Exeter Hospital, Exeter: 2 patients (Dr A Hong)

Royal Free Hospital, London: 2 patients (Dr T Meyer)

The James Cook University Hospital: 2 patients (Dr A Rathmell)

Churchill Hospital, Oxford: 1 patient (Dr Protheroe)

Ipswich Hospital, Ipswich: 1 patient (Dr J Le Vay)

Mid Kent Oncology Centre, Maidstone: 1 patient (Dr Beesley)

Scunthorpe General Hospital, Scunthorpe: 1 patient (Dr T Sreenivasan)

PET Centers

The Clinical PET Centre, Guy's & St Thomas' (Dr M O'Doherty, Dr S Hain)

Institute of Nuclear Medicine, Middlesex (Professor P Ell, Dr S Hain)

Paul Strickland Scanner Centre, Mt Vernon Hospital (Dr WL Wong)

The Manchester PET Centre, Christie Hospital (Mr D Hastings)

John Mallard Scottish PET Centre, Aberdeen Royal Infirmary (Dr A Welch)

Addenbrookes Hospital, Cambridge (Dr H Taylor)

Royal Marsden Hospital, Sutton (Dr G Cook, Dr V Lewington)

Rigshospitalet, Copenhagen

MRC CTU Staff

Trial manager: Lisa McDonald (previously Sharon Naylor, Neil Kelk, Rob Owens, Montse Wells); Data manager: Philip Pollock (Neil Kelk, Rob Owens, Montse Wells, Lisa McDonald); Statisticians: Sarah Kirk, Sally Stenning.

	NOTES

 
Supported by a grant from Cancer Research UK.

Presented in part at ECCO 2005 and the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, June 2-6, 2006.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted October 3, 2006; accepted April 24, 2007.

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