Metaxa's Thromboprophylaxis Program in Oncological & Surgical Patients
Conditions: Thrombosis, Solid Cancer
Sponsor: Metaxa Hospital

MeTHOS 
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MeTHOS PROTOCOL SYNOPSIS: OBSERVATIONAL STUDY 
 
 
 
Title: 
Metaxa's Thromboprophylaxis program 
in Oncological & Surgical patients 
Short Title 
MeTHOS 
Protocol Date: 
December 2018 
Study Principal Investigators 
Spyridon Xynogalos, MD, sxyn@otenet.gr 
Panagiotis Manikis, MD , paniman14@gmsil.com 
Co- Investigator 
Nikolaos Ziras , MD, zirasngr@otenet.gr 
Konstantinos Ntatsis 
George Vorias 
Sub – Investigators 
Evangelos Fergadis 
Iovatso Hristos 
David Simeonidis 
Orestis Sidiripoulos 
Georgia Migga 
Chrysa Kapsokoli 
Maria Leonti 
Evridiki Maslimoglou 
Emmanouil Mpakalinis 
 
 
 
 
 
 
 
 
 
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PROTOCOL SYNOPSIS 
Study 
Metaxa's Thromboprophylaxis program 
Title 
in Oncological & Surgical patients 
Study Rationale 
Venous thromboembolism (VTE) is common in cancer patients, with the 
Introduction 
risk being 4- to 7-fold higher compared with noncancer patients. [1 ]. 
VTE is associated with increased mortality, morbidity, [2,3] and burden 
on health care resources. [4]. The risk of recurrence and bleeding 
complications are major concerns during anticoagulant therapy, as up to 
9% of cancer patients with VTE develop recurrent thrombotic events, 
despite treatment with low-molecular-weight heparin (LMWH), [5–8]. 
Consequently, more effective prevention measures, especially during 
high-risk circumstances such as the postoperative period, may improve 
outcomes in these patients. 
  
Cancer patients 
undergoing 
surgery treatment 
 
It has been well established that major surgery itself increases the risk of 
VTE even in the absence of cancer. [9]. Historical data from 1970s and 
1980s using routine screening procedures reported a 37% incidence of 
deep vein thrombosis (DVT) following general surgery in patients with 
cancer, in contrast to an estimated risk of 20% in patients without cancer. 
 
[10]. However, changes in surgical techniques, use of perioperative 
chemotherapy, and the practice of early postoperative mobilization with 
increased awareness of perioperative VTE likely have altered VTE 
incidence over time. 
 
The absolute VTE risk varies with the type of surgery, including site, 
technique (e.g., open vs. laparoscopic approach), duration of surgery, 
type of anesthesia, the presence of postoperative infection and 
immobilization, and patients’ comorbidities (e.g., body mass index [BMI] 
and previous history of VTE). Surgeries for resection of malignant 
tumors are associated with a particularly high risk of VTE likely because 
of the extensive vascular injury from tumor invasion and dissection as 
well as lengthy operation time, and in some cases, residual tumor or nodal 
mass continues to cause venous compression and stasis. Prolonged 
postoperative immobility is also quite common in these patients. 
 
The risk of thrombosis is not only increased during the immediate 
postoperative period but also extends at least up to 30 days or even longer 
after surgery. In the @RISTOS study that prospectively followed 2,373 
patients who underwent surgery for cancer, 40% of symptomatic VTE 
occurred more than 3 weeks after surgery and 46% of deaths were due to 
fatal pulmonary embolism (PE). [11] The investigators of the @RISTOS 
study found that a previous history of VTE, anesthesia lasting 2 hours or 
longer, bed rest for 4 days or longer, advanced tumor stage, and age 60 
years or older were significant risk factors for VTE. Similarly, in the 
Million Women Study, the incidence of symptomatic VTE was observed 
to peak at 3 weeks postoperatively for all surgeries, but the risk remained 
  
 
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Pharmacological 
Prophylaxis for 
cancer patients 
undergoing 
surgery 
 
 
high up to 4 to 12 months for cancer patients.[12]. Relative to patients 
without cancer, the risk of VTE after surgery for cancer was 91-fold 
higher at 6 weeks, 53-fold at 7 to 12 weeks, and 34- fold at 4 to 12 months 
after surgery. 
  
Estimated risk of venous thromboembolism associated with various 
types of surgery 13 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacological Prophylaxis 
 
Studies in the late 1980s and early 1990s showed that pharmacological 
prophylaxis reduces the risk of postoperative VTE by 60% compared with 
no prophylaxis.[14-17] 
 
LMWH is generally the preferred choice of anticoagulant over UFH based 
on its ease of administration (once daily vs. twice to three times per day 
for UFH) and lower risk of heparin-induced thrombocytopenia (HIT). 
 
Cancer patients may also tolerate higher doses of LMWH 
without increasing the bleeding risk further.[18] 
 
The optimal duration of thromboprophylaxis after cancer surgery has not 
been established and the available data are limited to major abdominal 
and pelvic surgery. Although studies have shown that a longer duration of 
prophylaxis up to 1 month after major abdominal and pelvic surgery can 
further reduce the risk of VTE compared with standard duration (typically 
while in hospital or up to 7–10 days) [19-21] 
 
In the ENOXACAN II trial, patients who received extended 
thromboprophylaxis (ETP) with LMWH up to 30 days after open surgery 
for abdominal and pelvic cancer had a 60% VTE risk reduction (95% CI: 
10–82%), compared with those who received standard duration of 6 to 
10 days (4.8 vs. 12%; p = 0.02).[19] 
 
These findings are supported by a recent meta-analysis of seven RCTs 
and prospective studies which concluded that ETP is associated with a 
significant risk reduction of all VTE (2.6 vs. 5.6%; (RR: 0.44, 95% CI: 
 
 
 
 
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0.28–0.70) and proximal DVT (1.4 vs. 2.8%; RR: 0.46, 95% CI: 0.23– 
 
0.91). [22] 
 
 
 
 
 
Consensus guidelines on primary thromboprophylaxis in cancer patients 
undergoing surgery 
  
 
 
 
 
 
Guidelines for 
 
thromboprophylax 
is for cancer 
patients 
undergoing 
 
surgery 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Introduction for 
cancer patients 
undergoing 
chemotherapy 
  
 
 
 
 
 
 
 
 
 
 
 
 
Venous Thromboembolism (VTE) is a frequent malignancy complication 
which often results in serious health deterioration and death. The risk of 
deep vein thrombosis (DVT) and pulmonary embolism (PE) is 
considerably higher in cancer patients, compared to general population 
four to seven times [23, 24]. Venous thromboembolism is the second 
leading cause of death in patients with cancer and overall mortality is 
increased among patients who have both conditions. [25, 26, 27] 
 
Evidences suggest that Thromboembolism risk could be cancer related, 
patient related or treatment related. This risk is highest for patients with 
certain types of solid tumors (stomach, pancreas, lung, gynecologic, 
bladder, testicular) and hematologic cancers and is increased for patients 
who are receiving chemotherapy 6.5 times [28] or radiotherapy, who 
have undergone operative procedures, who have metastatic disease, or 
who have inherited thrombophilias. Studies have indicated that the 
mechanisms of this effect may include mucin production by tumors, 
exposure of tissue factor rich surfaces and tissue factor bearing 
microparticles, cysteine proteinase production leading to thrombin 
generation, and local hypoxia. [28,29,30] 
 
The development of VTE in cancer patients is associated with several 
adverse consequences including worsened short- and long-term prognosis 
and survival, mortality, morbidity, chemotherapy postponement, potential 
hospitalization, need for long-term anticoagulation with attendant 
bleeding complications and high rates of recurrent VTE [31,32]. In 
addition, VTE leads to significant consumption of health care resources; 
 
[33]. Therefore the optimal prevention and treatment of VTE are crucial 
components of patient care in this population. Currently, 
Low!Molecular! Weight Heparin (LMWH), is the gold standard for the 
CAT management for the last 15 years [34-36] 
 
Moreover, in a variety of high-risk thrombosis clinical settings, LMWHs 
agents are safe and effective in preventing VTE [37-38]. Multiple 
randomized trials of thromboprophylaxis have been conducted focusing 
on ambulatory cancer patients receiving chemotherapy [39-40] . ESMO 
and ASCO current guidelines suggest considering thromboprophylaxis 
in high-risk ambulatory cancer patients with LMWHs. 
  
 
 
 
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Several contemporary studies have investigated independent predictors 
for VTEs in patients actively receiving chemotherapy leading to the 
development of risk models for identifying patients at highest risk. [41] 
The Khorana model is a validated scoring system that utilizes specific 
patient characteristics and laboratory values to stratify patients into low, 
intermediate, or high risk for venous thromboembolism; 
  
Moreover , chemotherapy and thrombosis for over three decades, it 
remains an underappreciated risk that has not been routinely incorporated 
into thrombosis risk assessment models.[42] . Cytotoxic chemotherapy 
has a multifactorial contribution to the risk of thrombosis. It induces 
vascular injury through apoptosis. In the case of cisplatin, this leads to 
release of prothrombotic particles that trigger thrombin generation via 
tissue factor independent mechanisms along with drastically increased 
vWF activity. Other agents, like 5-FU, also drive thrombin formation in 
combination with depleted protein C activity. L-asparaginase 
administration is tied to drastically decreased protein C, protein S, and 
antithrombin levels, creating a prothrombotic milieu through loss of 
anticoagulant factors. VEGF inhibition does not directly lead to 
thrombosis, but instead ‘primes’ the endothelium through a VEGF starved 
state to be more susceptible to injury. Additionally, platelet activation 
through PAR-1 and increased Gp llb/llla activity in the case of 
immunomodulatory agents or increased vWF among others in the case of 
small molecule inhibitors contributes to this ‘primed’ state.[43-81] 
 
Cancer patients undergoing systemic treatment for their malignancy are 
among the highest risk populations for thromboembolic complications; 
often, the treatment itself contributes to this risk. Recognition of the 
antineoplastic agents most likely to cause thrombosis can help raise 
provider awareness and lead to earlier diagnosis and treatment. 
 
In our approach, we will protect our patient taking under consideration 
their treatment (surgery either chemotherapy ) 
  
 
Study Objective 
In this study we will collect Real World Data of our clinical practice 
regarding Thromboprophylaxis in high thrombotic risk solid tumors 
patients undergoing surgical and /or chemotherapeutical treatment, for 
one year following the protocol initiation date. 
 
• 
Specifically we will focus on the following : 
 
• 
Number of thrombotic events 
 
• 
Anti-thrombotic management dosage & duration 
 
• 
Any bleedings related to anticoagulation 
 
• 
Patients’ adherence and compliance 
  
 
 
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Study Design 
This is a prospective, phase IV, observational, non-interventional cohort 
study that aims to record the daily clinical practice regarding 
thromboprophylaxis in high thrombotic risk cancer patients (under surgry 
or chemotherapy) initiated December 2018 for a year time. 
Patients demographic data, cancer type and stage, anticoagulant treatment 
dose & duration, efficacy (VTE events), safety (bleedings) and 
information about adherence will be collected; more than one outcomes 
could be recorded. 
Subject Completion/Withdrawal 
Subjects may withdraw from the study at any time without prejudice to 
their care. They may also be discontinued from the study at the discretion 
of the Investigator for lack of adherence to study treatment or visit 
schedules, AEs, or due to termination of study observation period. The 
Investigator may also withdraw subjects who violate the study plan, or to 
protect the subject for reasons of safety or for administrative reasons. It 
will be documented whether or not each subject completes the clinical 
study. If the Investigator becomes aware of any serious, related adverse 
events after the subject completes or withdraws from the study, they will 
be recorded in the source documents and on the CRF. 
Clinical Adverse Events 
Clinical adverse events (AEs) will be monitored throughout the study. 
Adverse Event Reporting 
Since the study procedures are not greater than minimal risk, SAEs are not 
expected. If any unanticipated problems related to the research involving 
risks to subjects or others happen during the course of this study 
(including SAEs) these will be reported in accordance with current 
regulations. AEs that are not serious but that are notable and could involve 
risks to subjects will be summarized in narrative format. 
Authorized staff will perform periodic site visits to review CRFs for 
completeness, but will have no direct access to patient records; although 
they could request further information from the hospital staff. The 
anonymized data will be collated centrally and entered into an electronic 
database using double data entry where appropriate. Any discrepancies 
identified by electronic logic checks and will be resolved using data 
clarification forms sent to sites. 
Ethics committee approval will be obtained where approval of a 
prospective non-interventional study is required. This study will be 
conducted in full accordance all applicable Research Policies and 
Procedures and all applicable laws and regulations. The investigators will 
perform the study in accordance with this protocol, will obtain consent, 
and will report unanticipated problems involving risks to subjects or 
others in accordance with Policies and Procedures and all regulatory 
 
 
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requirements. Collection, recording, and reporting of data will be accurate 
and will ensure the privacy, health, and welfare of research subjects 
during and after the study. 
  
Subject Population Inclusion Criteria 
key criteria for 
1. Patients who were diagnosed with histological confirmed high 
Inclusion and 
thrombotic risk cancers (GI, thoracic, gynecologic and 
Exclusion: 
genitourinary) undergoing surgery 
2. Age ≥ 18 years 
3. ECOG 0-2 
4. Life expectancy >6 months 
5. Signed informed consent 
Exclusion Criteria 
1. Patients who were not diagnosed with histological confirmed high 
thrombotic risk cancers (GI, thoracic, gynecologic and 
genitourinary) undergoing surgery 
2. Age < 18 years 
3. ECOG >2 
4. Life expectancy <6 months 
5. Not signed informed consent 
  
 
Study Duration 
Each subject’s participation will last from inclusion (enrolment visit) to 
follow up visit (if applicable; four weeks post hospital discharge) 
The entire study is expected to last by the end of 2019 
Study Phases 
(1) Screening: screening for eligibility, obtaining consent and administer 
Screening 
thromboprophylaxis 
Study 
(2) Observation Period : monitoring subjects over treatment time 
Treatment 
(3) Follow-up Phase (only if applicable e.g. by the end of treatment 
Follow-Up 
period) 
Efficacy 
•  Symptomatic/Suspected    vein    thromboembolism,    including 
Evaluations 
pulmonary embolism and deep vein thrombosis 
Confirmation of symptomatic PE requires symptoms of PE and one of the 
following findings 
 
1. A (new) intraluminal filling defect in (sub) segmental or 
more proximal branches on spiral CT scan; 
 
2. A (new) intraluminal filling defect or an extension of an 
existing defect or a new sudden cut-off of vessels on the 
pulmonary angiogram; 
  
 
 
 
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3. A (new) considerable perfusion defect (~ 75% of a segment) 
with a local normal ventilation result (high-probability) on 
ventilation/perfusion lung scintigraphy (V/Q scan); 
 
4. An inconclusive lung scan accompanied by documentation 
of (new) DVT in the lower extremities e.g., by 
compression ultrasound or venography. 
 
• 
Confirmation of symptomatic DVT requires symptoms of DVT and: 
  
1. A (new) noncompressible venous segment on ultrasonography 
 
• 
Incidental PE with one of the following: 
 
1. A (new) intra-luminal filling defect on CT scan, MRI scan, or 
pulmonary angiogram; 
 
• 
An inconclusive lung scan accompanied by documentation of 
(new) DVT in the lower extremities e.g., by compression 
ultrasound or venography. 
 
• 
Fatal PE is: 
 
1. PE based on objective diagnostic testing or autopsy or 
 
2. death not attributed to a documented cause and for which DVT/PE 
cannot be ruled out 
 
• 
Incidental DVT with the following finding: 
 
Confirmation of recurrent incidental DVT requires inconclusive or no-
symptoms of DVT and: 
 
1. A (new) noncompressible venous segment on ultrasonography 
  
 
 
 
Safety Evaluations Major, clinically relevant non-major bleeding, and minor bleeding 
 
Major bleeding will be defined as overt bleeding associated with: a fall in 
hemoglobin of 2 g/dL or more, or leading to a transfusion, or bleeding 
that occurs in a critical site or contributing to death. 
 
• 
Bleeding in a critical area or organ such as: 
Retroperitoneal 
 
Intracranial 
Intraocular 
 
 
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Intraspinal 
 
Intra-articular 
Pericardial 
Intramuscular with compartment syndrome 
 
• 
A clinically overt bleeding event 
 
that is associated with a fall in hemoglobin of 2.0 g/dL (>1.24 
mMol/L) or more, or 
 
leading to a transfusion of ≥ 2 units of packed red blood cells or whole 
blood. 
 
• 
Bleeding contributing to death 
 
Other clinically relevant non-major bleeding will be defined as overt 
bleeding not meeting the criteria for major bleeding but associated with 
medical intervention, unscheduled contact (visit or telephone call) with a 
physician, (temporary) cessation of study treatment, or associated with 
discomfort for the patient such as pain, or impairment of activities of daily 
life. All other bleeding events will be classified as minor 
  
 
Statistical And 
Descriptional statistical analysis will be performed for all study data along 
 
Analytic Plan 
with epidemiology methods. Continuing parameters will be presented 
with standards descriptional statistical measures (mean values, median 
values, percentages etc.) and the results will be presented accordingly into 
tables. For more complex correlations we will use, among other methods, 
chi-square tests, ANOVA and t-tests, in order to evaluate the relationships 
between different patient and disease characteristics, such as: 
 
• 
Number of patients enrolled 
 
• 
Tumor characteristics 
 
• 
Co-morbidities 
 
• 
Type of Surgical operation 
 
• 
Type of antineoplastic treatment 
 
• 
Type of thromboprophylaxis therapy 
 
• 
Therapy outcomes 
 
• 
Number of therapy disruptions for any reason 
 
• 
Complications (AE- SAE) 
 
and to present them, accordingly. Due to the fact that this is an 
observational study the results of all correlations will be carefully 
discussed and will be used only to assess hypotheses. 
  
REFERENCES 
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APPENDIX 
 
1. 
Informed Consent Form (in Greek: ΕΝΤΥΠΟ ΣΥΓΚΑΤΑΘΕΣΗΣ ΜΕΤΑ ΑΠΟ ΕΝΗΜΕΡΩΣΗ) 
 
2. 
Case Report Form (In Greek: ΕΝΤΥΠΟ ΑΝΑΦΟΡΑΣ ΠΕΡΙΣΤΑΤΙΚΟΥ) 
 
 
Metaxa Hospital - Observational Study, December 2018