ABSTRACT screening for previously undiagnosed malignancy in patients with

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
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