- Email: [email protected]
Additional testing following screening strategies for occult malignancy diagnosis in patients with unprovoked venous thromboembolism
Accepted Manuscript Additional testing following screening strategies for occult malignancy diagnosis in patients with unprovoked venous thromboembolism
Philippe Robin, Pierre-Yves Le Roux, Emmanuelle Le Moigne, Benjamin Planquette, Nathalie Prévot-Bitot, Pierre-Marie Roy, Jean Pastre, Adel Merah, Francis Couturaud, Grégoire Le Gal, Pierre-Yves Salaun PII: DOI: Reference:
S0049-3848(17)30302-X doi: 10.1016/j.thromres.2017.04.022 TR 6638
To appear in:
Thrombosis Research
Received date: Revised date: Accepted date:
2 February 2017 7 April 2017 22 April 2017
Please cite this article as: Philippe Robin, Pierre-Yves Le Roux, Emmanuelle Le Moigne, Benjamin Planquette, Nathalie Prévot-Bitot, Pierre-Marie Roy, Jean Pastre, Adel Merah, Francis Couturaud, Grégoire Le Gal, Pierre-Yves Salaun , Additional testing following screening strategies for occult malignancy diagnosis in patients with unprovoked venous thromboembolism. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Tr(2017), doi: 10.1016/j.thromres.2017.04.022
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ACCEPTED MANUSCRIPT TITLE PAGE Article title: Additional testing following screening strategies for occult malignancy diagnosis in patients with unprovoked venous thromboembolism.
Name of authors : Philippe Robin, MD1, Pierre-Yves Le Roux, MD1, Emmanuelle Le Moigne,
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MD2, Benjamin Planquette, MD3, Nathalie Prévot-Bitot, MD4, Prof Pierre-Marie Roy, MD5, Jean Pastre, MD3, Adel Merah, MD6, Prof Francis Couturaud, MD2, Prof Grégoire Le Gal, MD7, Prof
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Pierre-Yves Salaun, MD1.
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Authors’affiliations:
1 Service de Médecine Nucléaire, EA 3878 (GETBO) IFR 148, Centre Hospitalier Universitaire de
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Brest, Université de Bretagne Occidentale, Brest, France,
2 Département de Médecine Interne et Pneumologie, EA 3878, CIC INSERM 1412, Centre
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Hospitalier Universitaire de Brest, Université de Bretagne Occidentale, Brest, France,
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3 Service de Pneumologie, Hôpital Européen Georges Pompidou, AP-HP; Université Paris Descartes, Sorbonne Paris Cité, INSERM UMR-S 1140, Paris, France,
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4 Service de Médecine Nucléaire, Inserm U1059, Centre Hospitalier Universitaire de Saint-Etienne, Université Jean Monnet ; Saint-Etienne, France; 5 Département de médecine d’urgences, Centre Hospitalier Universitaire d’Angers, Angers, France, 6 Service de médecine vasculaire et thérapeutique, Inserm CIC 1408, Centre Hospitalier Universitaire de Saint-Etienne, Saint- Etienne, France, 7 Department of Medicine, Ottawa Hospital Research Institute at the University of Ottawa, Ottawa, Canada.
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ACCEPTED MANUSCRIPT Running Head: Additional tests following occult cancer screening
Corresponding author: Prof Pierre-Yves Salaun
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Service de Médecine Nucléaire, EA 3878 (GETBO) IFR 148, Centre Hospitalo-Universitaire de Brest
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Université de Bretagne Occidentale
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2, avenue Foch 29609 Brest Cedex, France
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Phone number: + 33 2 98 22 33 27
e-mail: [email protected]
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First author:
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Fax number: + 33 2 98 22 39 64
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Dr Philippe Robin
Service de Médecine Nucléaire, EA 3878 (GETBO) IFR 148,
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Centre Hospitalo-Universitaire de Brest Université de Bretagne Occidentale 2, avenue Foch
29609 Brest Cedex, France
Phone number: + 33 2 98 22 33 27 Fax number: + 33 2 98 22 39 64
e-mail: [email protected]
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ABSTRACT 18
F-Fluorodesoxyglucose Positron-Emission-Tomography combined with Computed-Tomography
(FDG PET/CT) might be an attractive tool for cancer screening in patients with venous thromboembolism (VTE), allowing non-invasive whole-body imaging. One of the frequent criticisms
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to the use of FDG PET/CT for screening is the potential for false positive results leading to unnecessary/invasive investigations.
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Our aim was to compare the frequency and invasiveness of additional testing following extensive and
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limited screening strategies for occult malignancy in patients with unprovoked VTE.
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We analysed patients included in the MVTEP study, a randomized trial that compared a screening strategy based on FDG-PET/CT with a limited screening strategy for occult malignancy diagnosis in
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patients with unprovoked VTE. All additional diagnostic procedures following screening were
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recorded and classified as invasive or non invasive.
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A total of 394 patients were analysed. Additional diagnostic procedures realized in patients of each group consisted of 59 tests in patients of the FDG PET/CT group versus 53 tests among the patients
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from the limited screening group (p= 0.65). Overall, 45 (22.8%) patients in the FDG PET/CT group underwent additional diagnostic tests, versus 32 (16.2%) in the limited screening group (absolute risk difference +6.6%, 95% CI -1.3 to +14.4%, p=0.13). Sixteen (8.1%) patients in the FDG PET/CT group underwent invasive procedures, versus 6 (3%) in the limited screening group (absolute risk difference +5.1%, 95% CI +0.5 to +10.0%, p=0.03).
We found no statistical difference in the number of additional procedures following each screening strategy. However, a higher number of invasive tests were performed in the FDG PET/CT group.
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ACCEPTED MANUSCRIPT HIGHLIGHTS - Venous thromboembolism can occur as the first manifestation of an occult malignancy. - Concern for the use of FDG PET/CT for screening is the risk for unnecessary additional tests. - No difference of additional procedures following each screening strategy was observed.
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- Higher number of invasive tests in the FDG PET/CT arm.
KEYWORDS
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Positron Emission Tomography
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Occult cancer Screening strategy
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Venous thromboembolism
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ABBREVIATIONS
- FDG PET/CT: 18F-Fluorodesoxyglucose Positron-Emission-Tomography combined with Computed-
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Tomography
- US: ultrasonography
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- MRI: Magnetic Resonance Imaging
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- VTE: VenousThromboembolism
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INTRODUCTION Venous thromboembolism (VTE) can occur as the first manifestation of an underlying occult malignancy.1 Previous studies reported a 6% to 15% incidence of cancer in the year following the diagnosis of an unprovoked venous thromboembolism episode (ie, venous thromboembolism not
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provoked by a major risk factor).2-8 Screening for occult malignancy at the time of a venous thromboembolism is appealing, with the hope to be able to detect and treat these malignancies as early
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as possible in order to improve prognosis. Different screening strategies have been proposed.9-12
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Because all types and locations of cancer may be found in patients with venous thromboembolism, many investigations would have to be performed, resulting in expensive, invasive and time-
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consuming screening strategies.10 Clear guidelines for the investigation of occult malignancy after unprovoked venous thromboembolism are not yet available. 18
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F-Fluorodesoxyglucose Positron-Emission Tomography combined with low-dose Computed
Tomography (FDG PET/CT) is routinely used for the diagnosis, staging and restaging of various
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malignancies.13, 14 It might offer an attractive alternative allowing non-invasive whole body imaging.
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We recently reported the result of a multicenter open-label randomized trial comparing limited screening to limited screening plus FDG PET/CT in patients with unprovoked VTE. The study failed
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to demonstrate a significant increase in the rate of occult cancer detection in the FDG PET/CT arm at inclusion, which was the primary outcome. However, the rate of cancer diagnosis was 5.6% in the limited screening plus FDG PET/CT, vs. 2.0% in the limited screening arm. We also found a significantly lower incidence of cancer diagnosis during the two-year follow-up period among patients randomized to the limited screening plus FDG PET/CT strategy.15 Another finding was a lower overall prevalence of cancer than previously described (6%, vs. 10% in a previous systematic review)2, which could account for our negative result. This lower prevalence was in line with other recent studies on cancer screening in VTE.9, 11 A better selection of patients for screening might lead to more efficient screening strategies, and FDG PET/CT appears promising in this regards. However, one of the frequent criticisms to the use of extensive screening strategies, particularly to the use of FDG PET/CT for screening, is the potential for false positive results (‘incidentalomas’), 5
ACCEPTED MANUSCRIPT leading to unnecessary investigations. Previous non-randomized studies reported positive predictive values for FDG PET/CT ranging from 4 to 54%,16-18 but data on additional testing following a positive or suspicious FDG PET/CT finding remain limited, and no comparison with the rate of additional testing following limited screening is available. To fill this knowledge gap, we assessed whether or not the frequency and invasiveness of additional
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testing following two screening strategies for occult malignancy were different in a population of patients enrolled in a prospective, multicenter, randomized, controlled study comparing a limited
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screening strategy with a strategy combining limited screening and FDG PET/CT in patients with
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unprovoked venous thromboembolism.
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METHODS Study population This is a post-hoc analysis of an open label, multicenter, randomized study that compared a screening strategy based on FDG PET/CT with a limited screening strategy for detection of occult malignant
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disease in patients with unprovoked VTE. Methods have been previously described in detail. 15 Patients aged 18 years or older, diagnosed with unprovoked venous thromboembolism were invited to
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participate in the study if they did not present any exclusion criteria: ongoing pregnancy, active
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malignancy (defined as known malignancy, active and/or treated during the previous five years), unable or unwilling to give consent.
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Study design
Patients were randomized into two arms. In the limited screening arm, patients underwent medical
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history, complete physical examination, routine laboratory tests including complete blood count, erythrocyte sedimentation rate or C-reactive protein, transaminases, alkaline phosphatase, calcium,
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chest X-ray, and recommended age- and gender-specific cancer screening tests (i.e. prostate-specific
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antigen in men over 50 years of age, mammography in women over 50 years of age and Pap-smear in all women). In the limited plus FDG PET/CT arm, patients underwent the same limited screening and
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a FDG PET/CT, which was performed in all patients in this arm, regardless of the results of the limited screening tests. FDG PET-CT were performed using Gemini GXLi, Philips in Brest University Hospital; Discovery ST, General Electric in Angers University Hospital; Biograph 6 LSO Pico 3D HI-REZ, Siemens Medical in Saint Etienne University Hospital; Gemini GXL, Philips and Discovery 690, General Electric in Paris (HEGP). Patients fasted for at least 6 hours before PET acquisitions, and blood glucose had to be less than 7 mmol/L before injection of 3 to 5 MBq/kg of 18F-FDG. Intravenous injection was followed by a period of approximately 60 minutes when the patients remained in a quiet room. Computed tomography was performed from mid-forehead to the feet in normal shallow respiration using a low-dose setting. Intravenous iodinated contrast was not administered. Data obtained from the CT-scan were used for attenuation correction of PET data and
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ACCEPTED MANUSCRIPT for fusion with attenuation-corrected PET images. In case of positive finding on initial screening, patients were referred for appropriate diagnostic procedures at the discretion of the treating physician. All patients underwent clinical follow-up every 6 months for 24 months. Medical history and physical examination were performed, and in case of new symptoms or clinical signs, further testing was ordered. Information on any investigation for suspected malignancy requested at any time during
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follow-up was collected. All patients provided written informed consent. The study was conducted in accordance with the
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ethical principles set forth in the Declaration of Helsinki, Good Clinical Practice, and relevant French
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regulations regarding ethics and data protection. The protocol was approved for all study sites by our institutional Ethics committee (Comité de Protection des Personnes Ouest VI, 2008-541). The study
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was registered on clinicaltrials.gov (NCT00964275).
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Additional diagnostic procedures
All additional diagnostic procedures performed following positive findings at screening were recorded
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and classified as invasive or non invasive. Diagnostic procedures performed during the remainder of
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follow-up were not considered in this study.
An additional diagnostic procedure was considered as invasive when the body was entered by a
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device, tube or instrument, with potential procedure-related complications, e.g. any biopsy, surgery, image-guided biopsy, upper and lower gastrointestinal endoscopy, endoscopic ultrasonography, needle cytology. A contrario, an additional diagnostic procedure that did not meet the definition above was considered as non invasive, e.g., thoracic, abdominal or pelvic imaging: ultrasonography (US), computed tomography (CT), magnetic resonance imaging (MRI), nuclear imaging, tumor markers, and additional laboratory tests.
Statistical Analysis General characteristics of the population were described using median (IQR) or numbers and proportions, as appropriate. The number of additional diagnostic procedures was determined in each group, and compared using a t-test. Moreover, the proportion of patients who underwent additional 8
ACCEPTED MANUSCRIPT diagnostic test and invasive test was determined in each group, and compared using a test. We also estimated the absolute risk difference between the groups along with its 95% confidence interval. Positive predictive value (PPV, define as the number of true positives divided by the number of investigated patients) and false positive rate (FPR, define as the number of false positives divided by the number of investigated patients) of additional tests performed in each group were calculated.
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Statistical analysis was done with IBM SPSS Statistics (version 23).
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RESULTS Between March 3, 2009, and August 18, 2012, 748 patients were assessed for eligibility, and 399 were included and randomized to one of the two study groups. 200 patients were allocated to the FDG PET/CT group, and 199 to the limited screening group. Five patients, three in the FDG PET/CT group
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and two in the limited screening group, withdrew consent and refused further use of their study data.
presented in table 1. Median age was 63 years (IQR 49–76).
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Table 1 General characteristics of the population
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Thus, 197 patients were analysed in each group. General characteristics of the population are
FDG PET/CT
Limited screening
(n=197)
(n=197)
64 (48 – 77) 145 (74%)
62 (50 – 75) 147 (75%)
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Characteristics
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Age, years Older than 50 years Sex Male Female Venous thromboembolism - Deep vein thrombosis
Pulmonary embolism ± deep vein thrombosis
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No venous thromboembolism
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-
105 (53%) 92 (47%)
102 (52%) 95 (48%)
42 (21%) 153 (78%) 2 (1%)
29 (15%) 168 (85%) 0
Tobacco use 32 (16%) Oral contraceptives 12 (6%) Familial history of cancer 61 (31%) Previous malignancy 12 (6%) Prior venous thromboembolism 60 (30%) Alcohol intoxication 21 (11%) Asbestos exposition 14 (7%) Asthenia 21 (11%) Anorexia 3 (2%) 18 18 Data are median (IQR) or n (%). F-FDG= F-fluorodeoxyglucose.
35 (18%) 13 (7%) 67 (34%) 10 (5%) 56 (28%) 13 (7%) 13 (7%) 31 (16%) 4 (2%)
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Proportion of additional tests at screening in both groups Additional diagnostic procedures realized in patients of each group consisted of 59 tests in patients of the FDG PET/CT group versus 53 tests among the patients from the limited screening group (p= 0.65). Overall, 45 patients (22.8%) in the FDG PET/CT group underwent additional diagnostic tests,
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versus 32 (16.2%) in the limited screening group (absolute risk difference +6.6%, 95% CI -1.3 to +14.4%, p=0.13). Among patients included in the FDG PET/CT arm, the main indication for
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additional tests was clinical findings in 4, laboratory results in 21, imaging/cytology results in 2, and
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FDG PET/CT abnormalities in 18. In the control arm, the main indication for additional tests was clinical findings in 11, laboratory results in 20, imaging/cytology results in 1.
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Sixteen patients (8.1%) in the FDG PET/CT group underwent invasive additional diagnostic procedures, versus 6 (3%) in the limited screening group (absolute risk difference +5.1%, 95% CI
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+0.5 to +10.0%, p=0.03). No procedure-related complications of additional tests were recorded in both groups. Additional invasive and non-invasive diagnostic procedures ordered in each arm are
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described in table 2.
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ACCEPTED MANUSCRIPT Table 2 Additional diagnostic procedures performed in the limited screening plus FDG PET/CT vs. limited screening. Limited screening + FDG PET/CT (45
Limited screening (32 patients receiving 53 additional tests)
Non invasive procedures (n=43) US abdomen and pelvis: n=21* CT thorax, abdomen and pelvis: n= 9 US Neck: n=5 MRI abdomen: n=1 MRI pelvis: n=1 MRI prostate: n=1 Somatostatin receptor scintigraphy: n=1 Thyroid markers: n=1 Tumor markers: n=1 Bone radiography: n=1 Red cell mass value: n=1*
Non invasive procedures (n=47) US abdomen and pelvis: n=27 CT thorax, abdomen and pelvis: n= 12 FDG PET/CT: n=3 Pulmonary function test: n=2 MRI liver: n=1 Tumor markers: n=1 US Neck: n=1
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Invasive procedures (n=6) Colon surgery: n=1* Endometrium biopsy: n=1* Esophagogastroduodenoscopy: n=1 Liver biopsy: n=1* Prostate biopsy: n=1* Colonoscopy: n=1
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Invasive procedures (n=16) Prostate biopsy: n=3*** Colonoscopy: n=3* Pharyngeal biopsy: n=2* Esophagogastroduodenoscopy: n=2 Endoscopic pancreas US: n=2* Pleural biopsy: n=1* Needle cytology of thyroid nodule: n=1 Orchidectomy: n=1* Lymphadenopathy biopsy: n=1*
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patients receiving 59 additional tests)
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(* Procedure leading to cancer diagnosis, Procedure leading to alternative benign diagnosis)
Results of additional tests at screening in both groups A cancer was diagnosed for 11 patients among the 45 patients of the FDG PET/CT group who underwent additional diagnostic procedures, 4 patients with early-stage cancer and 7 patients with advanced-stage cancer. The PPV of additional tests in the limited screening + FDG PET/CT group at screening was 24.4% (11/45, 95% CI, 14.2% - 38.7%) and the FPR was 75.6% (34/45, 95% CI, 61.3% - 85.8%). Out of the 34 remaining patients, 7 patients underwent an invasive diagnostic procedure (2 lower intestinal endoscopies, 3 upper gastrointestinal endoscopies, 1 thyroid fine needle aspiration, 1 nasopharyngeal biopsy), which led for 4 patients to an alternative benign diagnosis such as colon diverticulitis and hyperplasic polyp in 2 patients, gastric lipoma in 1 patient, benign thyroid
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ACCEPTED MANUSCRIPT nodule in 1 case. For 3 patients, the invasive diagnostic procedures (2 upper gastrointestinal endoscopies and 1 nasopharyngeal biopsy) did not highlight any abnormality. A cancer was diagnosed for 4 patients among 32 patients of the limited screening group who underwent additional diagnostic procedures, 2 patients with early-stage cancer and 2 patients with advanced-stage cancer.The PPV of additional tests in the limited screening group was 12.5% (4/32,
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95% CI, 5% - 28.1%) and the FPR was 87.5% (28/32, 95% CI, 71.9% - 95%). Out of the 28 remaining patients, 2 patients underwent an invasive diagnostic procedure (1 lower intestinal
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endoscopy and 1 upper gastrointestinal endoscopy), which led for these 2 patients to an alternative
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benign diagnosis such as inflammatory changes of the transverse colon in 1 patient and oesophagitis in 1 patient.
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Overall, 7 patients of the FDG PET/CT group underwent additional invasive procedures that did not lead to cancer diagnosis, versus 2 in the limited screening group (absolute risk difference +2.5%, 95%
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CI -6.2 to +0.6%, p=0.17).
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DISCUSSION In the present ancillary analysis of the MVTEP trial,15 evaluating the frequency and invasiveness of additional testing following screening strategies for occult malignancy, we observed an absolute 6.6% (95% CI -1.3 to +14.4%) increase in the proportion of patients who underwent additional testing in patients after a limited screening plus FDG PET/CT, as compared with limited screening. Moreover, a
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higher number of invasive tests were performed in the FDG PET/CT group.
FDG PET/CT is a powerful tool routinely used for the diagnosis, staging and restaging of cancer.13, 14
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However, it has not been widely evaluated for cancer screening in selected patient with risk factors.19
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Cancer screening in a selected population may provide an effective intervention that could potentially influences the outcome of patient. Unprovoked VTE may occur as the first manifestation of an
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underlying occult malignancy,1 and offers a good selected population for cancer screening. However, in a multicenter open-label randomized trial comparing limited screening to limited screening plus FDG PET/CT in patients with unprovoked VTE, we failed to demonstrate a significant increase in the
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rate of occult cancer detection in the FDG PET/CT arm at inclusion. Similarly, in the SOME study aiming to assess the efficacy of adding a comprehensive CT to a limited screening strategy for occult
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cancer in patients with unprovoked VTE, Carrier et al. found that routine screening with CT of the abdomen and pelvis did not provide a clinically significant benefit.9 However, in our study, we demonstrated that the risk of subsequent cancer diagnosis was lower in patients who had negative initial screening that included FDG PET/CT than in patients who had negative initial limited screening.15 The main concern raised by physicians regarding the use of FDG PET/CT for cancer screening is the potential high rate of additional explorations required in light of the FDG PET/CT findings, particularly the need for invasive tests such as biopsies or surgical procedures with important side effects.
In our study, we did not find a statistical difference between limited screening group and limited screening plus FDG PET/CT group for additional testing, regarding the number of additional test 14
ACCEPTED MANUSCRIPT performed (59 additional tests in the FDG PET/CT group vs. 53 additional tests in the limited screening group), and regarding the number of patients in whom additional procedure performed (22.8% patients in the FDG PET/CT group vs. 16.2% patients in the limited screening group, p=0.13). In the SOME study, Carrier et al. reported a lower rate of patients in whom additional test were performed after the extensive screening (limited screening plus CT): 14.9% in comparison to 22.8%
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in our study (limited screening plus FDG PET/CT), although the rate of additional testing was similar in the control arm of the two studies: 14.4% vs 16.2%.9 Interestingly, these rates are lower than those
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published in a cross-sectional retrospective review of 1192 consecutive patients who underwent
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whole-body CT screening at a stand-alone for-profit outpatient facility. Indeed, they concluded that there was a high prevalence (86%) of reported relevant findings with whole-body CT screening and
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that 37% of patients received recommendations for follow-up examinations.20 When focusing on patients who had invasive tests, we found a higher number of patient explored with
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an invasive procedure in the FDG PET/CT arm (16 patients in the FDG PET/CT group vs. 6 patients in the limited screening group, absolute risk difference +5.1%, 95% CI +0.5 to +10.0%, p=0.03).
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However, it is noteworthy that among the 16 patients of the FDG PET/CT group who underwent an
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invasive test, 9 explorations led to a cancer diagnosis and 4 to an alternative benign disease. Only 3 patients had an invasive diagnostic procedure that did not highlight any disease: one had a biopsy
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(nasopharyngeal biopsy), and 2 others underwent an upper gastrointestinal endoscopy. No patient experienced complications of additional testing. Altogether, despite a higher number of patients who underwent invasive investigations in the FDG PET/CT arm, these additional tests sometimes led to an underlying disease (diagnosis of a malignant or benign condition).
Our study has some limitations. First, the lower than expected incidence of cancer limited the statistical power of our study. The sample size was relatively small, resulting in wide confidence intervals, and potentially in our inability to detect rarer events, such as complications resulting from additional testing. Along the same line, we are aware that the number of invasive procedures in each group is quite small which makes results of comparisons less convincing, even if statistically significant. Secondly, the open-label design might have had an impact on our results: clinicians were 15
ACCEPTED MANUSCRIPT aware of the allocated arm and might have preferred to order additional tests to patients from the limited screening arm, in order not to miss an occult cancer, knowing that these patients would not undergo the FDG PET/CT. This might have artificially decreased the difference in the rate of additional testing between the two arms. Moreover, it might have led to underestimate the rate of additional testing following the limited work up in the extensive screening arm, if physicians were
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reassured and did not order additional testing while awaiting the upcoming FDG PET/CT. However this bias would not explain the effectiveness of invasive exploration realized according to FDG
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PET/CT findings, which led to a negative biopsy in only one patient. Thridly, 23 patients of the
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limited screening + FDG PET/CT group did not receive FDG PET/CT at inclusion. However a per-
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protocol analysis did not change the results (results not shown).
In conclusion, in this post-hoc analysis we did not find any significant difference regarding the
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number of additional tests following a limited screening strategy as compared with a screening strategy comprising a FDG PET/CT. However, we observed a higher number of invasive tests
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following the limited screening plus FDG PET/CT.
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ACCEPTED MANUSCRIPT ACKNOWLEDGMENTS
Funding source: The study was supported by grants from the "Programme Hospitalier de Recherche Clinique" (French Department of Health), and the sponsor was the University Hospital of Brest. G. Le Gal holds a University of Ottawa Department of Medicine Chair in Diagnosis of Venous Thromboembolism, a Clinician-Scientist award from the Heart and Stroke Foundation of Ontario, and
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None of the authors declare any competing financial interests.
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CONFLICT OF INTEREST DISCLOSURES
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an Early Research Award from the Government of Ontario.
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and recommendations in 1192 patients. Radiology. 2005; 385-394.
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ACCEPTED MANUSCRIPT HIGHLIGHTS - Venous thromboembolism can occur as the first manifestation of an occult malignancy. - Concern for the use of FDG PET/CT for screening is the risk for unnecessary additional tests. - No difference of additional procedures following each screening strategy was observed.
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- Higher number of invasive tests in the FDG PET/CT arm.
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Philippe Robin, Pierre-Yves Le Roux, Emmanuelle Le Moigne, Benjamin Planquette, Nathalie Prévot-Bitot, Pierre-Marie Roy, Jean Pastre, Adel Merah, Francis Couturaud, Grégoire Le Gal, Pierre-Yves Salaun PII: DOI: Reference:
S0049-3848(17)30302-X doi: 10.1016/j.thromres.2017.04.022 TR 6638
To appear in:
Thrombosis Research
Received date: Revised date: Accepted date:
2 February 2017 7 April 2017 22 April 2017
Please cite this article as: Philippe Robin, Pierre-Yves Le Roux, Emmanuelle Le Moigne, Benjamin Planquette, Nathalie Prévot-Bitot, Pierre-Marie Roy, Jean Pastre, Adel Merah, Francis Couturaud, Grégoire Le Gal, Pierre-Yves Salaun , Additional testing following screening strategies for occult malignancy diagnosis in patients with unprovoked venous thromboembolism. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Tr(2017), doi: 10.1016/j.thromres.2017.04.022
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT TITLE PAGE Article title: Additional testing following screening strategies for occult malignancy diagnosis in patients with unprovoked venous thromboembolism.
Name of authors : Philippe Robin, MD1, Pierre-Yves Le Roux, MD1, Emmanuelle Le Moigne,
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MD2, Benjamin Planquette, MD3, Nathalie Prévot-Bitot, MD4, Prof Pierre-Marie Roy, MD5, Jean Pastre, MD3, Adel Merah, MD6, Prof Francis Couturaud, MD2, Prof Grégoire Le Gal, MD7, Prof
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Pierre-Yves Salaun, MD1.
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Authors’affiliations:
1 Service de Médecine Nucléaire, EA 3878 (GETBO) IFR 148, Centre Hospitalier Universitaire de
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Brest, Université de Bretagne Occidentale, Brest, France,
2 Département de Médecine Interne et Pneumologie, EA 3878, CIC INSERM 1412, Centre
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Hospitalier Universitaire de Brest, Université de Bretagne Occidentale, Brest, France,
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3 Service de Pneumologie, Hôpital Européen Georges Pompidou, AP-HP; Université Paris Descartes, Sorbonne Paris Cité, INSERM UMR-S 1140, Paris, France,
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4 Service de Médecine Nucléaire, Inserm U1059, Centre Hospitalier Universitaire de Saint-Etienne, Université Jean Monnet ; Saint-Etienne, France; 5 Département de médecine d’urgences, Centre Hospitalier Universitaire d’Angers, Angers, France, 6 Service de médecine vasculaire et thérapeutique, Inserm CIC 1408, Centre Hospitalier Universitaire de Saint-Etienne, Saint- Etienne, France, 7 Department of Medicine, Ottawa Hospital Research Institute at the University of Ottawa, Ottawa, Canada.
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ACCEPTED MANUSCRIPT Running Head: Additional tests following occult cancer screening
Corresponding author: Prof Pierre-Yves Salaun
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Service de Médecine Nucléaire, EA 3878 (GETBO) IFR 148, Centre Hospitalo-Universitaire de Brest
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Université de Bretagne Occidentale
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2, avenue Foch 29609 Brest Cedex, France
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Phone number: + 33 2 98 22 33 27
e-mail: [email protected]
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First author:
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Fax number: + 33 2 98 22 39 64
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Dr Philippe Robin
Service de Médecine Nucléaire, EA 3878 (GETBO) IFR 148,
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Centre Hospitalo-Universitaire de Brest Université de Bretagne Occidentale 2, avenue Foch
29609 Brest Cedex, France
Phone number: + 33 2 98 22 33 27 Fax number: + 33 2 98 22 39 64
e-mail: [email protected]
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ABSTRACT 18
F-Fluorodesoxyglucose Positron-Emission-Tomography combined with Computed-Tomography
(FDG PET/CT) might be an attractive tool for cancer screening in patients with venous thromboembolism (VTE), allowing non-invasive whole-body imaging. One of the frequent criticisms
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to the use of FDG PET/CT for screening is the potential for false positive results leading to unnecessary/invasive investigations.
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Our aim was to compare the frequency and invasiveness of additional testing following extensive and
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limited screening strategies for occult malignancy in patients with unprovoked VTE.
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We analysed patients included in the MVTEP study, a randomized trial that compared a screening strategy based on FDG-PET/CT with a limited screening strategy for occult malignancy diagnosis in
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patients with unprovoked VTE. All additional diagnostic procedures following screening were
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recorded and classified as invasive or non invasive.
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A total of 394 patients were analysed. Additional diagnostic procedures realized in patients of each group consisted of 59 tests in patients of the FDG PET/CT group versus 53 tests among the patients
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from the limited screening group (p= 0.65). Overall, 45 (22.8%) patients in the FDG PET/CT group underwent additional diagnostic tests, versus 32 (16.2%) in the limited screening group (absolute risk difference +6.6%, 95% CI -1.3 to +14.4%, p=0.13). Sixteen (8.1%) patients in the FDG PET/CT group underwent invasive procedures, versus 6 (3%) in the limited screening group (absolute risk difference +5.1%, 95% CI +0.5 to +10.0%, p=0.03).
We found no statistical difference in the number of additional procedures following each screening strategy. However, a higher number of invasive tests were performed in the FDG PET/CT group.
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ACCEPTED MANUSCRIPT HIGHLIGHTS - Venous thromboembolism can occur as the first manifestation of an occult malignancy. - Concern for the use of FDG PET/CT for screening is the risk for unnecessary additional tests. - No difference of additional procedures following each screening strategy was observed.
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- Higher number of invasive tests in the FDG PET/CT arm.
KEYWORDS
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Positron Emission Tomography
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Occult cancer Screening strategy
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Venous thromboembolism
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ABBREVIATIONS
- FDG PET/CT: 18F-Fluorodesoxyglucose Positron-Emission-Tomography combined with Computed-
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Tomography
- US: ultrasonography
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- MRI: Magnetic Resonance Imaging
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- VTE: VenousThromboembolism
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INTRODUCTION Venous thromboembolism (VTE) can occur as the first manifestation of an underlying occult malignancy.1 Previous studies reported a 6% to 15% incidence of cancer in the year following the diagnosis of an unprovoked venous thromboembolism episode (ie, venous thromboembolism not
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provoked by a major risk factor).2-8 Screening for occult malignancy at the time of a venous thromboembolism is appealing, with the hope to be able to detect and treat these malignancies as early
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as possible in order to improve prognosis. Different screening strategies have been proposed.9-12
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Because all types and locations of cancer may be found in patients with venous thromboembolism, many investigations would have to be performed, resulting in expensive, invasive and time-
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consuming screening strategies.10 Clear guidelines for the investigation of occult malignancy after unprovoked venous thromboembolism are not yet available. 18
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F-Fluorodesoxyglucose Positron-Emission Tomography combined with low-dose Computed
Tomography (FDG PET/CT) is routinely used for the diagnosis, staging and restaging of various
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malignancies.13, 14 It might offer an attractive alternative allowing non-invasive whole body imaging.
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We recently reported the result of a multicenter open-label randomized trial comparing limited screening to limited screening plus FDG PET/CT in patients with unprovoked VTE. The study failed
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to demonstrate a significant increase in the rate of occult cancer detection in the FDG PET/CT arm at inclusion, which was the primary outcome. However, the rate of cancer diagnosis was 5.6% in the limited screening plus FDG PET/CT, vs. 2.0% in the limited screening arm. We also found a significantly lower incidence of cancer diagnosis during the two-year follow-up period among patients randomized to the limited screening plus FDG PET/CT strategy.15 Another finding was a lower overall prevalence of cancer than previously described (6%, vs. 10% in a previous systematic review)2, which could account for our negative result. This lower prevalence was in line with other recent studies on cancer screening in VTE.9, 11 A better selection of patients for screening might lead to more efficient screening strategies, and FDG PET/CT appears promising in this regards. However, one of the frequent criticisms to the use of extensive screening strategies, particularly to the use of FDG PET/CT for screening, is the potential for false positive results (‘incidentalomas’), 5
ACCEPTED MANUSCRIPT leading to unnecessary investigations. Previous non-randomized studies reported positive predictive values for FDG PET/CT ranging from 4 to 54%,16-18 but data on additional testing following a positive or suspicious FDG PET/CT finding remain limited, and no comparison with the rate of additional testing following limited screening is available. To fill this knowledge gap, we assessed whether or not the frequency and invasiveness of additional
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testing following two screening strategies for occult malignancy were different in a population of patients enrolled in a prospective, multicenter, randomized, controlled study comparing a limited
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screening strategy with a strategy combining limited screening and FDG PET/CT in patients with
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unprovoked venous thromboembolism.
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METHODS Study population This is a post-hoc analysis of an open label, multicenter, randomized study that compared a screening strategy based on FDG PET/CT with a limited screening strategy for detection of occult malignant
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disease in patients with unprovoked VTE. Methods have been previously described in detail. 15 Patients aged 18 years or older, diagnosed with unprovoked venous thromboembolism were invited to
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participate in the study if they did not present any exclusion criteria: ongoing pregnancy, active
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malignancy (defined as known malignancy, active and/or treated during the previous five years), unable or unwilling to give consent.
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Study design
Patients were randomized into two arms. In the limited screening arm, patients underwent medical
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history, complete physical examination, routine laboratory tests including complete blood count, erythrocyte sedimentation rate or C-reactive protein, transaminases, alkaline phosphatase, calcium,
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chest X-ray, and recommended age- and gender-specific cancer screening tests (i.e. prostate-specific
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antigen in men over 50 years of age, mammography in women over 50 years of age and Pap-smear in all women). In the limited plus FDG PET/CT arm, patients underwent the same limited screening and
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a FDG PET/CT, which was performed in all patients in this arm, regardless of the results of the limited screening tests. FDG PET-CT were performed using Gemini GXLi, Philips in Brest University Hospital; Discovery ST, General Electric in Angers University Hospital; Biograph 6 LSO Pico 3D HI-REZ, Siemens Medical in Saint Etienne University Hospital; Gemini GXL, Philips and Discovery 690, General Electric in Paris (HEGP). Patients fasted for at least 6 hours before PET acquisitions, and blood glucose had to be less than 7 mmol/L before injection of 3 to 5 MBq/kg of 18F-FDG. Intravenous injection was followed by a period of approximately 60 minutes when the patients remained in a quiet room. Computed tomography was performed from mid-forehead to the feet in normal shallow respiration using a low-dose setting. Intravenous iodinated contrast was not administered. Data obtained from the CT-scan were used for attenuation correction of PET data and
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ACCEPTED MANUSCRIPT for fusion with attenuation-corrected PET images. In case of positive finding on initial screening, patients were referred for appropriate diagnostic procedures at the discretion of the treating physician. All patients underwent clinical follow-up every 6 months for 24 months. Medical history and physical examination were performed, and in case of new symptoms or clinical signs, further testing was ordered. Information on any investigation for suspected malignancy requested at any time during
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follow-up was collected. All patients provided written informed consent. The study was conducted in accordance with the
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ethical principles set forth in the Declaration of Helsinki, Good Clinical Practice, and relevant French
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regulations regarding ethics and data protection. The protocol was approved for all study sites by our institutional Ethics committee (Comité de Protection des Personnes Ouest VI, 2008-541). The study
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was registered on clinicaltrials.gov (NCT00964275).
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Additional diagnostic procedures
All additional diagnostic procedures performed following positive findings at screening were recorded
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and classified as invasive or non invasive. Diagnostic procedures performed during the remainder of
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follow-up were not considered in this study.
An additional diagnostic procedure was considered as invasive when the body was entered by a
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device, tube or instrument, with potential procedure-related complications, e.g. any biopsy, surgery, image-guided biopsy, upper and lower gastrointestinal endoscopy, endoscopic ultrasonography, needle cytology. A contrario, an additional diagnostic procedure that did not meet the definition above was considered as non invasive, e.g., thoracic, abdominal or pelvic imaging: ultrasonography (US), computed tomography (CT), magnetic resonance imaging (MRI), nuclear imaging, tumor markers, and additional laboratory tests.
Statistical Analysis General characteristics of the population were described using median (IQR) or numbers and proportions, as appropriate. The number of additional diagnostic procedures was determined in each group, and compared using a t-test. Moreover, the proportion of patients who underwent additional 8
ACCEPTED MANUSCRIPT diagnostic test and invasive test was determined in each group, and compared using a test. We also estimated the absolute risk difference between the groups along with its 95% confidence interval. Positive predictive value (PPV, define as the number of true positives divided by the number of investigated patients) and false positive rate (FPR, define as the number of false positives divided by the number of investigated patients) of additional tests performed in each group were calculated.
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Statistical analysis was done with IBM SPSS Statistics (version 23).
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RESULTS Between March 3, 2009, and August 18, 2012, 748 patients were assessed for eligibility, and 399 were included and randomized to one of the two study groups. 200 patients were allocated to the FDG PET/CT group, and 199 to the limited screening group. Five patients, three in the FDG PET/CT group
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and two in the limited screening group, withdrew consent and refused further use of their study data.
presented in table 1. Median age was 63 years (IQR 49–76).
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Table 1 General characteristics of the population
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Thus, 197 patients were analysed in each group. General characteristics of the population are
FDG PET/CT
Limited screening
(n=197)
(n=197)
64 (48 – 77) 145 (74%)
62 (50 – 75) 147 (75%)
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Characteristics
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Age, years Older than 50 years Sex Male Female Venous thromboembolism - Deep vein thrombosis
Pulmonary embolism ± deep vein thrombosis
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No venous thromboembolism
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105 (53%) 92 (47%)
102 (52%) 95 (48%)
42 (21%) 153 (78%) 2 (1%)
29 (15%) 168 (85%) 0
Tobacco use 32 (16%) Oral contraceptives 12 (6%) Familial history of cancer 61 (31%) Previous malignancy 12 (6%) Prior venous thromboembolism 60 (30%) Alcohol intoxication 21 (11%) Asbestos exposition 14 (7%) Asthenia 21 (11%) Anorexia 3 (2%) 18 18 Data are median (IQR) or n (%). F-FDG= F-fluorodeoxyglucose.
35 (18%) 13 (7%) 67 (34%) 10 (5%) 56 (28%) 13 (7%) 13 (7%) 31 (16%) 4 (2%)
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Proportion of additional tests at screening in both groups Additional diagnostic procedures realized in patients of each group consisted of 59 tests in patients of the FDG PET/CT group versus 53 tests among the patients from the limited screening group (p= 0.65). Overall, 45 patients (22.8%) in the FDG PET/CT group underwent additional diagnostic tests,
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versus 32 (16.2%) in the limited screening group (absolute risk difference +6.6%, 95% CI -1.3 to +14.4%, p=0.13). Among patients included in the FDG PET/CT arm, the main indication for
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additional tests was clinical findings in 4, laboratory results in 21, imaging/cytology results in 2, and
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FDG PET/CT abnormalities in 18. In the control arm, the main indication for additional tests was clinical findings in 11, laboratory results in 20, imaging/cytology results in 1.
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Sixteen patients (8.1%) in the FDG PET/CT group underwent invasive additional diagnostic procedures, versus 6 (3%) in the limited screening group (absolute risk difference +5.1%, 95% CI
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+0.5 to +10.0%, p=0.03). No procedure-related complications of additional tests were recorded in both groups. Additional invasive and non-invasive diagnostic procedures ordered in each arm are
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described in table 2.
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ACCEPTED MANUSCRIPT Table 2 Additional diagnostic procedures performed in the limited screening plus FDG PET/CT vs. limited screening. Limited screening + FDG PET/CT (45
Limited screening (32 patients receiving 53 additional tests)
Non invasive procedures (n=43) US abdomen and pelvis: n=21* CT thorax, abdomen and pelvis: n= 9 US Neck: n=5 MRI abdomen: n=1 MRI pelvis: n=1 MRI prostate: n=1 Somatostatin receptor scintigraphy: n=1 Thyroid markers: n=1 Tumor markers: n=1 Bone radiography: n=1 Red cell mass value: n=1*
Non invasive procedures (n=47) US abdomen and pelvis: n=27 CT thorax, abdomen and pelvis: n= 12 FDG PET/CT: n=3 Pulmonary function test: n=2 MRI liver: n=1 Tumor markers: n=1 US Neck: n=1
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Invasive procedures (n=6) Colon surgery: n=1* Endometrium biopsy: n=1* Esophagogastroduodenoscopy: n=1 Liver biopsy: n=1* Prostate biopsy: n=1* Colonoscopy: n=1
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Invasive procedures (n=16) Prostate biopsy: n=3*** Colonoscopy: n=3* Pharyngeal biopsy: n=2* Esophagogastroduodenoscopy: n=2 Endoscopic pancreas US: n=2* Pleural biopsy: n=1* Needle cytology of thyroid nodule: n=1 Orchidectomy: n=1* Lymphadenopathy biopsy: n=1*
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patients receiving 59 additional tests)
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(* Procedure leading to cancer diagnosis, Procedure leading to alternative benign diagnosis)
Results of additional tests at screening in both groups A cancer was diagnosed for 11 patients among the 45 patients of the FDG PET/CT group who underwent additional diagnostic procedures, 4 patients with early-stage cancer and 7 patients with advanced-stage cancer. The PPV of additional tests in the limited screening + FDG PET/CT group at screening was 24.4% (11/45, 95% CI, 14.2% - 38.7%) and the FPR was 75.6% (34/45, 95% CI, 61.3% - 85.8%). Out of the 34 remaining patients, 7 patients underwent an invasive diagnostic procedure (2 lower intestinal endoscopies, 3 upper gastrointestinal endoscopies, 1 thyroid fine needle aspiration, 1 nasopharyngeal biopsy), which led for 4 patients to an alternative benign diagnosis such as colon diverticulitis and hyperplasic polyp in 2 patients, gastric lipoma in 1 patient, benign thyroid
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ACCEPTED MANUSCRIPT nodule in 1 case. For 3 patients, the invasive diagnostic procedures (2 upper gastrointestinal endoscopies and 1 nasopharyngeal biopsy) did not highlight any abnormality. A cancer was diagnosed for 4 patients among 32 patients of the limited screening group who underwent additional diagnostic procedures, 2 patients with early-stage cancer and 2 patients with advanced-stage cancer.The PPV of additional tests in the limited screening group was 12.5% (4/32,
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95% CI, 5% - 28.1%) and the FPR was 87.5% (28/32, 95% CI, 71.9% - 95%). Out of the 28 remaining patients, 2 patients underwent an invasive diagnostic procedure (1 lower intestinal
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endoscopy and 1 upper gastrointestinal endoscopy), which led for these 2 patients to an alternative
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benign diagnosis such as inflammatory changes of the transverse colon in 1 patient and oesophagitis in 1 patient.
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Overall, 7 patients of the FDG PET/CT group underwent additional invasive procedures that did not lead to cancer diagnosis, versus 2 in the limited screening group (absolute risk difference +2.5%, 95%
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CI -6.2 to +0.6%, p=0.17).
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DISCUSSION In the present ancillary analysis of the MVTEP trial,15 evaluating the frequency and invasiveness of additional testing following screening strategies for occult malignancy, we observed an absolute 6.6% (95% CI -1.3 to +14.4%) increase in the proportion of patients who underwent additional testing in patients after a limited screening plus FDG PET/CT, as compared with limited screening. Moreover, a
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higher number of invasive tests were performed in the FDG PET/CT group.
FDG PET/CT is a powerful tool routinely used for the diagnosis, staging and restaging of cancer.13, 14
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However, it has not been widely evaluated for cancer screening in selected patient with risk factors.19
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Cancer screening in a selected population may provide an effective intervention that could potentially influences the outcome of patient. Unprovoked VTE may occur as the first manifestation of an
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underlying occult malignancy,1 and offers a good selected population for cancer screening. However, in a multicenter open-label randomized trial comparing limited screening to limited screening plus FDG PET/CT in patients with unprovoked VTE, we failed to demonstrate a significant increase in the
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rate of occult cancer detection in the FDG PET/CT arm at inclusion. Similarly, in the SOME study aiming to assess the efficacy of adding a comprehensive CT to a limited screening strategy for occult
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cancer in patients with unprovoked VTE, Carrier et al. found that routine screening with CT of the abdomen and pelvis did not provide a clinically significant benefit.9 However, in our study, we demonstrated that the risk of subsequent cancer diagnosis was lower in patients who had negative initial screening that included FDG PET/CT than in patients who had negative initial limited screening.15 The main concern raised by physicians regarding the use of FDG PET/CT for cancer screening is the potential high rate of additional explorations required in light of the FDG PET/CT findings, particularly the need for invasive tests such as biopsies or surgical procedures with important side effects.
In our study, we did not find a statistical difference between limited screening group and limited screening plus FDG PET/CT group for additional testing, regarding the number of additional test 14
ACCEPTED MANUSCRIPT performed (59 additional tests in the FDG PET/CT group vs. 53 additional tests in the limited screening group), and regarding the number of patients in whom additional procedure performed (22.8% patients in the FDG PET/CT group vs. 16.2% patients in the limited screening group, p=0.13). In the SOME study, Carrier et al. reported a lower rate of patients in whom additional test were performed after the extensive screening (limited screening plus CT): 14.9% in comparison to 22.8%
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in our study (limited screening plus FDG PET/CT), although the rate of additional testing was similar in the control arm of the two studies: 14.4% vs 16.2%.9 Interestingly, these rates are lower than those
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published in a cross-sectional retrospective review of 1192 consecutive patients who underwent
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whole-body CT screening at a stand-alone for-profit outpatient facility. Indeed, they concluded that there was a high prevalence (86%) of reported relevant findings with whole-body CT screening and
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that 37% of patients received recommendations for follow-up examinations.20 When focusing on patients who had invasive tests, we found a higher number of patient explored with
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an invasive procedure in the FDG PET/CT arm (16 patients in the FDG PET/CT group vs. 6 patients in the limited screening group, absolute risk difference +5.1%, 95% CI +0.5 to +10.0%, p=0.03).
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However, it is noteworthy that among the 16 patients of the FDG PET/CT group who underwent an
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invasive test, 9 explorations led to a cancer diagnosis and 4 to an alternative benign disease. Only 3 patients had an invasive diagnostic procedure that did not highlight any disease: one had a biopsy
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(nasopharyngeal biopsy), and 2 others underwent an upper gastrointestinal endoscopy. No patient experienced complications of additional testing. Altogether, despite a higher number of patients who underwent invasive investigations in the FDG PET/CT arm, these additional tests sometimes led to an underlying disease (diagnosis of a malignant or benign condition).
Our study has some limitations. First, the lower than expected incidence of cancer limited the statistical power of our study. The sample size was relatively small, resulting in wide confidence intervals, and potentially in our inability to detect rarer events, such as complications resulting from additional testing. Along the same line, we are aware that the number of invasive procedures in each group is quite small which makes results of comparisons less convincing, even if statistically significant. Secondly, the open-label design might have had an impact on our results: clinicians were 15
ACCEPTED MANUSCRIPT aware of the allocated arm and might have preferred to order additional tests to patients from the limited screening arm, in order not to miss an occult cancer, knowing that these patients would not undergo the FDG PET/CT. This might have artificially decreased the difference in the rate of additional testing between the two arms. Moreover, it might have led to underestimate the rate of additional testing following the limited work up in the extensive screening arm, if physicians were
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reassured and did not order additional testing while awaiting the upcoming FDG PET/CT. However this bias would not explain the effectiveness of invasive exploration realized according to FDG
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PET/CT findings, which led to a negative biopsy in only one patient. Thridly, 23 patients of the
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limited screening + FDG PET/CT group did not receive FDG PET/CT at inclusion. However a per-
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protocol analysis did not change the results (results not shown).
In conclusion, in this post-hoc analysis we did not find any significant difference regarding the
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number of additional tests following a limited screening strategy as compared with a screening strategy comprising a FDG PET/CT. However, we observed a higher number of invasive tests
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following the limited screening plus FDG PET/CT.
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ACCEPTED MANUSCRIPT ACKNOWLEDGMENTS
Funding source: The study was supported by grants from the "Programme Hospitalier de Recherche Clinique" (French Department of Health), and the sponsor was the University Hospital of Brest. G. Le Gal holds a University of Ottawa Department of Medicine Chair in Diagnosis of Venous Thromboembolism, a Clinician-Scientist award from the Heart and Stroke Foundation of Ontario, and
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None of the authors declare any competing financial interests.
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CONFLICT OF INTEREST DISCLOSURES
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an Early Research Award from the Government of Ontario.
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Furtado CD, Aguirre DA, Sirlin CB, et al. Whole-body CT screening: spectrum of findings
and recommendations in 1192 patients. Radiology. 2005; 385-394.
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ACCEPTED MANUSCRIPT HIGHLIGHTS - Venous thromboembolism can occur as the first manifestation of an occult malignancy. - Concern for the use of FDG PET/CT for screening is the risk for unnecessary additional tests. - No difference of additional procedures following each screening strategy was observed.
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- Higher number of invasive tests in the FDG PET/CT arm.
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