ABSTRACT diagnosis of venous thromboembolism (VTE) comprises both

ABSTRACT

Objective: To evaluate the efficacy of extensive
diagnostic screening for malignancy in patients with a first episode of
unprovoked DVT on improving cancer related morbidity and mortality by way of
earlier diagnosis and treatment.

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Design: A multi-study review

Methods: A PubMed search of RCTs was conducted
using search terms “venous thromboembolism” AND “cancer” AND “unprovoked” AND
“occult”, Humans, Ages 19+, publications within the last 5 years, randomized
control trial

Results: Two RCTs and one Cochrane review were
reviewed for evidence regarding the use of extensive diagnostic screening. All
three studies demonstrated low efficacy. No adverse effects were seen.

Conclusion: At this time extensive diagnostic
screening for previously undiagnosed malignancy in patients with a first
episode idiopathic VTE is ineffective in improving cancer related morbidity and
mortality by way of early diagnosis and treatment. However, extensive screening
such as the use of PET/CT might be useful in a more selected population of
patients with a high risk of cancer as shown in the second RCT I looked at.

 

 

Introduction

The diagnosis of venous thromboembolism (VTE)
comprises both pulmonary embolism and deep-vein thrombosis. VTE is the third
most common reported cardiovascular event. Any VTE that is caused by an
anticipated hypercoagulable state such as trauma, surgery, prolonged bedrest,
pregnancy or malignancy is known as a provoked VTE. For all others which are
not associated with strong risk factors we label these cases as unprovoked
cases of VTE. Cancer is known to cause a hypercoagulable state in patients for
many reasons. Tumor cells are clot promoting and lead to the activation of the
clotting cascade. They play a role in promoting the generation of thrombin and
fibrin, stimulate the production of platelets, or thrombocytosis, leukocytes
and endothelial cells which then go on to expose their cellular pro-coagulant
features.

                  This
hypercoagulable state of malignancy has been known as early as 1865 when Armand
Trousseau, a French physician first described a clinical associated between
thrombosis and yet undiagnosed cancer. Trousseau’s Sign of Malignancy is a
medical sign involving episodes of vessel inflammation due to blood clots,
which are recurrent or appearing in different locations over time in
association with cancer. Trousseau himself presented with a VTE before he was
later diagnosed with gastric cancer.  Currently it is known that thrombotic events
are the second leading cause of death in cancer patients after death directly
caused by the cancer itself. It is also known that approximately twenty percent
of patients with symptomatic deep vein thrombosis already have a known active
malignancy. So if this is true, what can we conclude about those patients
without a known malignancy at the time of first episode unprovoked VTE?

                  Previous
studies have shown that up to ten percent of patients with unprovoked VTE end
up receiving a diagnosis of cancer within a year after diagnoses of VTE, and
that more than sixty percent of occult cancers diagnoses are made shortly after
the diagnosis of an unprovoked VTE. Over the first year after a diagnosed
unprovoked VTE, the incidence rate of cancer diagnosis gradually declines and
returns to the risk of the general population after twelve months. 

                  Currently
the recommendation for a standard workup after first episode of unprovoked DVT
includes a full history and physical exam, some routine blood work, and a chest
x ray. Recommendations also include those made by the USPSTF which are specific
to age and gender i.e. prostate exam, mammography etc. While an extensive
diagnostic screening has the potential to alter the clinical course and
therefore the prognosis for many patients, it is invasive and costly.
Therefore, how aggressive should we be in screening for occult cancers in
patients who present with unprovoked venous thromboembolism? My objective
during this project is to look through the data to see if more extensive
screening truly is effective in reducing morbidity and mortality compared to
the current standard of care.

 

RESEARCH QUESTION

Is extensive screening testing for
previously undiagnosed malignancy in patients with a first episode of
unprovoked VTE significant in improving cancer related morbidity and
mortality?

 

LITERATURE REVIEW

A PubMed search was conducted in December 2017,
using the search terms “venous thromboembolism” AND “cancer” AND “unprovoked”
AND “occult”. This first search yielded 164 articles. The search limits “humans”,
“Ages 19+”, “publications within the last 5 years”, and “randomized control
trial” which limited my results to eleven studies. Three articles from my
search were then chosen from the final eleven. One two of which are original
RCTs and the third being a Cochrane review article which compares my first two
studies with an additional two studies.

 

SUMMARY OF KEY ARTICLES

Study #1

 

Carrier et. Al. Screening for Occult Cancer
in Unprovoked Venous Thromboembolism. N Engl J Med. 2015 Aug
20;373(8):697-704. doi: 10.1056/NEJMoa1506623. Epub 2015 Jun 22.

A multicenter, open-label, randomized control
trial which took place in nine hospitals in Canada from 2008-2014. The
objective of this study was to assess the efficacy of a screening strategy for
occult cancer with comprehensive CT of the abdomen and pelvis in patients with
first episode of unprovoked venous thromboembolism.

 

Validity assessment: Study Design: The study included 854 participants across nine hospital centers in
Canada. The study included people with a new diagnosis of first unprovoked VTE (lower
extremity DVT, PE or both). Unprovoked VTE defined as VTE in absence of known
overt active cancer, current pregnancy, thrombophilia (hereditary or acquired),
previous unprovoked VTE or a temporary predisposing factor in the previous 3
months, including paralysis, paresis or plaster immobilization of the legs,
confinement to bed for ? 3 days or major surgery. Exclusion criteria included
< 18 years, refusal or inability to provide informed consent, allergy to contrast media, creatinine clearance < 60 mL per minute, claustrophobia or agoraphobia, weight > 130 kg, ulcerative colitis or glaucoma. The average
age for the screening + CT group was 53.4 years, with a standard deviation of
14.2. and the screening only group was 53.7 years with a standard deviation of
13.8 years.  Study Conduct: Screening procedure: complete history
and physical examination, measurement of complete blood counts and serum
electrolyte and creatinine levels, liver-function testing and chest
radiography. Sex-specific screening conducted if it had not been performed in
previous year. Breast examination, mammography, or both performed in women >
50 years of age and Pap testing and a pelvic examination performed in women
18-70 years of age who had never been sexually active. Prostate examination,
PSA test, or both performed in men aged > 40 years. Also comprehensive CT of
abdomen and pelvis (virtual colonoscopy and gastroscopy, biphasic enhanced CT
of liver, parenchymal pancreatography, and uniphasic enhanced CT of distended
bladder). Control Group: complete
history and physical examination, measurement of complete blood counts and
serum electrolyte and creatinine levels, liver-function testing and chest
radiography. Sex-specific screening conducted if it had not been performed in
previous year. Breast examination, mammography, or both performed in women >
50 years of age and Pap testing and a pelvic examination performed in women
18-70 years of age who had ever been sexually active. Prostate examination, PSA
test, or both performed in men aged > 40 years. Patients were seen again for one year follow up after visits  Study Results: Primary outcomes: newly diagnosed cancer during the
follow-up period in people who had a negative screening result for occult
cancer.

In the
primary outcome analysis, 4 occult cancers (29%) were missed by the
limited screening strategy, whereas 5 (26%) were missed by the strategy of
limited screening plus CT (P=1.0). There was no significant difference
between the two study groups in the meantime to a cancer diagnosis (4.2
months in the limited-screening group and 4.0 months in the
limited-screening-plus-CT group, P=0.88) or in cancer-related mortality
(1.4% and 0.9%, P=0.75).

Secondary outcomes: total number of occult cancers diagnosed and total number of early cancers
(T1-2, N0, M0 according to the World Health Organization TNM classification
system) diagnosed by occult-cancer screening and during subsequent 1-year
follow-up, 1-year cancer-related mortality, 1-year overall mortality, time to
cancer diagnosis and incidence of recurrent VTE.

Study Critique:

This study had many strengths including a low
risk of selection bias due to computer generated numbers for patients. There
was also a low risk of detection bias as outcome assessors were blinded to allocation
of study participants. Reporting bias was also of low risk as primary and
secondary outcome measures were clearly specified and reported. However, it was
noted that there were lower than normal rates of cancer detected in this study
just by virtue of chance which could have led to a discrepancy in outcomes

 

Study #2

 

Robin et. Al. Limited screening with versus
without (18)F-fluorodeoxyglucose PET/CT for occult malignancy in unprovoked
venous thromboembolism. An open-label randomized controlled trial. Lancet
Oncol. 2016 Feb;17(2):193-199. doi: 10.1016/S1470-2045(15)00480-5. Epub
2015 Dec 8.

 

Open label, multicenter randomized study which
took place in France across four hospital centers. The objective of this study
was to compare a screening strategy based on (18)F-FDG PET/CT with a limited
screening strategy for detection of malignant disease in patients with
unprovoked venous thromboembolism.

 

Validity Assessment

Study Design: This study
included 195 participants across 5 hospital centers in Italy. The average age
in the extensive screening group was 69.3 years, while the average age in the
control group was 69.0 years. There were 54 Males and 44 Females in the
extensive screening group, 47 males and 50 females in the control group.
Inclusion criteria included patients with an objectively diagnosed, first
episode of unprovoked VTE in whom routine initial screening for cancer was
negative. Exclusion criteria included history of previous documented episodes
of VTE, aged < 18 years, pregnant, unable to attend follow-up visits because of geographic inaccessibility, had known allergy to contrast medium or had a CT scan of torso for any reasons within 6 months from presentation. Study Conduct:  Screening procedure: extensive screening with mandatory CT scan of thorax, abdomen and pelvis together with haemoccult test or any test at physician's discretion according to good clinical practice. Control: personalized strategy consisting of additional testing based on physicians' judgements and participants' preferences, including a 'no-further testing' option.   Duration: 3, 6, 12 and 24 months' follow-up in which participants were asked about general health, history of recent hospital admissions and occurrence of signs and symptoms suggestive of cancer. Cancer outcomes that presented during follow-up were detected based on clinical features that would prompt diagnostic imaging or cancers that were occasionally detected by screening that was independent of the diagnosis of VTE.   Study Results: Primary outcomes: proportion of people with a cancer diagnosis in each group after the initial screening assessment. Secondary outcomes: subsequent cancer diagnosis in people with negative initial screening, proportion of early-stage versus advanced-stage tumors at initial screening and during follow-up, overall mortality and cancer-related mortality during follow-up. After initial screening assessment, malignancy was diagnosed in: 11 (5.6%) of patients in the PET/CT group and 4 (2.0%) of patients in the limited screening group, p=0.07 At the initial screening assessment: 7/11 cancers in the PET/CT group (64%) were early stage compared to 2/4 cancers in the limited screening group, p=1.00 During follow-up: One (0.5%) occult malignancy was detected in the 186 patients with negative initial screening in the PET/CT group, compared with nine (4.7%) in the 193 patients in the limited screening group, p=0.01 Overall: 5/12 (42%) of cancers diagnosed in the PET/CT group were advanced stage compared with 7/13 (54%) in the limited screening group, p=0.70. Sixteen patients died during follow-up, eight in each group. Of these patients, two in the PET/CT group (1.0%) and five (2.5%) in the limited screening group had cancer related deaths. Screening for malignancy the addition of a (18)F-FDG PET/CT was not associated with a significantly higher rate of cancer diagnosis after unprovoked venous thromboembolism. However, the risk of subsequent cancer diagnosis was significantly lower in patients who had negative initial screening that included (18)F-FDG PET/CT than in patients who had negative initial limited screening. Study Critique: Weaknesses The incidence of cancer increases with age, but about 25% of the patient population were younger than 50 years, which could have partially account for the lower than normal rate of cancer in this study. This study had a broad definition of unprovoked VTE; they did not exclude patients with VTE while on oral estrogen contraceptives or after a long travel. These patients might also have a low risk of occult cancer. Researchers did not exclude patients with a previous history of VTE. Compliance rate with recommended limited screening tests was not optimum among participants. Unfortunately, there is limited availability of PET/CT scanners across institutions. There was also a high risk of detection bias due to lack of blinding of outcome assessors to patient allocation   Study #3   Robertson L, Yeoh SE, Stansby G, Agarwal R. Effect of testing for cancer on cancer- and venous thromboembolism (VTE)-related mortality and morbidity in people with unprovoked VTE. Cochrane Database of Systematic Reviews 2017, Issue 8   A systematic review of four primary studies. The objective of this review was to determine whether testing for undiagnosed cancer in people with a first episode of unprovoked VTE is effective in reducing cancer and VTE-related mortality and morbidity and to determine which tests for cancer are best at identifying treatable cancers early.       Studies: Randomized and quasi-randomized trials in which patients with an unprovoked VTE were allocated to receive specific tests for cancer or clinically indicated tests. Primary outcome measures included all-cause mortality, cancer-related mortality and VTE-related mortality Participants: Patients with a first episode of unprovoked VTE (DVT of the lower limb or PE) with no pre-existing or clinically apparent cancer diagnosis Interventions: Standard tests for cancer including CBC, Ca2+, LFT, urinalysis, CXR, CT imaging, mammogram, tumor markers, sputum cytology, U/S, PET, and colonoscopy vs. no tests or alternative tests   Methods: Cochrane Information Specialist (CIS) searched the Specialized Register – a database maintained by Cochrane constructed from weekly electronic searches of MEDLINE, Embase, CINAHL and AMED and hand searching of relevant journals.  The CIS also searched trial databases for ongoing and unpublished articles including: •       WHO international clinical trials registry platform •       clinicaltrials.gov •       ISRCTN registry Two review authors independently selected studies, assessed quality and extracted data. One review author entered the data while the other cross-checked data entry and resolved any discrepancies by consulting the source publication   The Studies:   A.    Study #1 Piccioli A, Lensing AWA, Prins MH, Falanga A, Scannapieco GL, Ieran M, et al. Extensive screening for occult malignant disease in idiopathic venous thromboembolism: a prospective randomized clinical trial. Journal of Thrombosis and Haemostasis 2004;2:884-9.   Randomized multicenter study published in 2004 of 201 patients without a known cancer diagnosis with acute unprovoked VTE. This study compared extensive screening for occult malignancy compared to testing at the physician's discretion. •       99 patients were randomized to the extensive screening group •       102 patients were randomized to the control group •       Extensive screening offered U/S and CT AP, double contrast barium swallowing, colonoscopy or sigmoidoscopy followed by a barium enema, hemoccult test, sputum cytology and tumor markers including CEA, ?-FP, and CA125. •       Women were also offered mammography and pap smears while men had transabdominal ultrasound of the prostate and PSA   All tests in this study were completed within a four-week period from the diagnosis of VTE. Participants in the control group were investigated at the physician's discretion. If the investigations suggested the presence of a malignant process, further investigations were performed according to current standards. Participants were followed up at 3, 12 and 24 months following the diagnosis of VTE. The primary outcome was cancer-related morbidity (a death due to a malignant disease itself) or death due to complications of diagnostic or surgical procedures performed to diagnose or treat cancer. A secondary outcome of this study consisted of the cluster of cancer-related mortality and documented residual malignancy or recurrent malignancy at 24 months. The authors also measured the frequency of an underlying cancer diagnosis including type and stage as well as mean time to cancer diagnosis.   Results: The Primary outcome: 2/99 participants in the extensive testing group died of cancer compared to 4/102 in the group who underwent tests at the physician's discretion (OR 0.51, 95% CI 0.09 to 2.82).   This study also looked at the specific locations of detected malignancies and there was no clear difference found in the detection of any particular cancer between study participants who underwent screening under the physician's discretion vs. extensive screening.   They compared characteristics of diagnosed cancers via early stage disease (T1 or T2 and M0, N0) between the two groups. Overall it was found that malignancies were less advanced in those participants who had undergone extensive screening. 9/13 patients diagnosed with cancer in the extensive screening group had T1-T2, M0, N0 stage malignancy compared to 2/10 participants who were diagnosed with T1-2, M0, N0 cancers in the control group (p=0.04), leading to a low quality of significance. There was no difference between groups in the detection of advanced stage cancers. Only one participant in the extensive screening group had stage T3 cancer vs. four patients in the control group (p=0.22)   This study also measured the time to cancer diagnosis from the time of objectively diagnosed VTE. There was a reported mean of one month in the extensive screening group compared to 11.6 months in the control group (p=<0.001). Cochrane was unable to obtain the standard deviation for these means as they were not listed in the study however they did not receive a response.   A.    Study #2 Prandoni P, Bernardi E, Valle FD, Visona A, Tropeano PF, Bova C, et al. Extensive computed tomography versus limited screening for detection of occult cancer in unprovoked venous thromboembolism: a multicenter, controlled, randomized clinical trial. Seminars in Thrombosis and Hemostasis 2016;42(8):884-90.   Randomized study in which 195 participants with a first episode of unprovoked VTE were randomized to extensive investigations (98 participants) or a discretionary diagnostic approach excluding CT scans (97 participants) •       Extensive screening included mandatory CT CAP together with fecal hemoccult testing or any test at physician's discretion according to good clinical practice. •       Participants allocated to the discretionary diagnostic approach or personalized strategy underwent additional testing based on physicians' judgements and participants' preferences, including a 'no-further testing' option.   Participants were followed at 3, 6, 12 and 24 months to document the incidence of newly discovered cancer and cancer-related mortality. The primary outcomes were cancer-related mortality (defined as death due to malignancy, or death due to the complications of the diagnostic or surgical procedures performed to diagnose or treat cancer) and incidence of newly discovered cancer. The secondary outcomes were cancer stage, using the tumors-nodes-metastases classification, at which tumors were diagnosed in the two study groups and the incidence of cancer-related mortality in the two randomization groups,   Results:   This study detected cancer in 2/98 participants in the extensive screening group and in 2/97 patients in the control group who were tested at the physician's discretion (OR 0.99, 95% CI 0.14 to 7.17).   The combined incidence of an underlying cancer diagnosis between these two studies (Piccioli and Prandoni) was 15/197 in the extensive screening group and 12/199 in the control group (OR 1.32, 95% CI 0.59 to 2.93; non-significant). Based off these studies was concluded that after 24 months of follow-up from time of VTE diagnosis the incidence of cancer was no different in the tested and control groups.   Neither Piccioli 2004b nor Prandoni 2016 measured the other studies included in the review's primary outcomes of all-cause mortality including those unrelated to cancer, and overall VTE-related mortality. They also did not measure the secondary outcomes of complications of anticoagulation treatment, adverse effects of cancer tests, or participant satisfaction/quality of life.   Overall between these two studies it was found that more extensive testing did not increase the incidence of an underlying cancer diagnosis. However, the time to cancer diagnosis was found to be shorter in participants undergoing extensive screening (a mean of one month with extensive tests versus 11 months with tests at the physician's discretion). However, researchers did not list the standard deviations for these means, and were not able to be contacted by Cochrane reviewers therefore the statistical significance of this could not be calculated.  The Piccioli study also found that more participants had a detection of early-stage cancer with extensive tests compared to people who were tested at the physician's discretion.   ANAYLYSIS     Conclusion/Discussion   Is extensive diagnostic testing for previously undiagnosed malignancy in patients with a first episode of idiopathic VTE effective in improving cancer related morbidity and mortality by way of early diagnosis and treatment? After reviewing the most up to date literature I have to say unfortunately no as of now. However, extensive screening such as the use of PET/CT might be useful in a more selected population of patients with a high risk of cancer as shown in study #2. Although statistical significance could not be calculated due to a missing standard deviation, the Piccioli study also found a much shorter mean time to cancer diagnoses in participants who underwent extensive screening with imaging compared to patients who underwent screening at their physician's discretion (1 month compared to 11 months)   For future studies it might be helpful to have a stricter selection criterion for RCTs and compare patients who were already under the care of a primary care physician prior to initial VTE and therefore, were more likely to have had routine blood work and imaging in comparison to those without care prior to VTE to see if this discrepancy in patients could have led to any bias.          

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