Clinical trial NCT00525057
Conditions: Bone Sarcoma Femur Fracture Lymphoma Metastatic Neoplasm Pathologic Fracture Plasma Cell Myeloma Soft Tissue Sarcoma
Sponsor: M.D. Anderson Cancer Center
Start date: 2006-07-07; Completion date: 2020-06-19
Enrollment: 65 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This trial studies how well dalteparin works in preventing deep vein thrombosis (DVT) (blood clots) in participants with cancer. Dalteparin is a blood thinner that can treat blood clots and may prevent them from forming.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the safety of dalteparin as prophylaxis against deep venous thrombosis (DVT) in orthopedic oncology patients.

II. To determine whether there are significantly increased bleeding complications at the surgical site after major oncologic operations in the lower extremity.

OUTLINE:

Participants receive dalteparin subcutaneously (SC) once daily (QD) starting 12-24 hours after surgery on post-operative day 1 until hospital discharge, about 7-10 days.

Arms: arm 1: Participants receive dalteparin SC QD starting 12-24 hours after surgery on post-operative day 1 until hospital discharge, about 7-10 days.
Interventions: intervention 1: Dalteparin
Intervention descriptions: intervention 1: Given SC

Protocol documents:
Prot_SAP_000.pdf: 
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Revised August 19, 2009 
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Purpose: 
 
 
1. The primary endpoint of the study would be to determine the safety of dalteparin 
as prophylaxis against deep venous thrombosis (DVT) in orthopaedic oncology 
patients.  Specifically, the goal of the study is to determine whether there are 
significantly increased bleeding complications at the surgical site after major 
oncologic operations in the lower extremity. 
 
a. The study would help establish specific parameters for use of dalteparin in 
complex orthopaedic oncology patients.  Not all patients would be 
appropriate for this medication, particularly those with massive hemorrhage 
during surgery and those with underlying coagulopathies. 
b. It is likely that patients requiring limited tumor excision, particularly those 
with metastatic carcinoma, would be ideal candidates for dalteparin therapy. 
c. Patients who require radical resections of tumor may need stricter 
guidelines for the safe use of the medication, since the potential for post-
operative bleeding may be greater. 
 
Hypotheses: 
 
1. Dalteparin may be used safely in complex group of patients such as orthopaedic 
oncology patients, provided that strict guidelines are followed with regard to 
indications for therapy. 
 
2. Patents with metastatic carcinoma affecting the osseous skeleton would be good 
candidates for treatment since they generally have limited surgical resections and 
a pre-disposition to formation of DVTs. 
 
3. The use of dalteparin would result in a low rate of DVTs that would compare 
favorably against historical controls. 
 
Introduction: 
 
It is well recognized that patients undergoing orthopaedic procedures such as total knee 
replacements and total hip replacements, are at increased risk of venous thrombo-
embolic events.1, 2  It is also known that cancer patients are at increased risk of venous 
thrombosis.3-5  There have been little written about venous thrombosis in cancer patients 
undergoing major resections and orthopaedic procedures in the lower extremities.  It is 
not well documented in the literature what the prevalence and extent of the problem is. 
 
The largest previous study was performed at Memorial Sloan-Kettering Cancer Center.  
This study focused on the role of mechanical compression boots in orthopaedic oncology 
patients.6  As expected, there is a high rate of proximal DVT’s in the thigh even with 
mechanical prophylaxis (17%).  This study did not address the potential use of low 
molecular weight heparins or other forms of anti-coagulation.  Preliminary results from a 
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follow-up study recently presented at the Musculoskeletal Tumor Society Meeting showed 
promising results with the use of dalteparin and a significant reduction in the DVT rate.7 
 
Although it would be preferable to improve the prophylaxis in this production, there is 
general concern among surgeons that the risk of bleeding would be high.  Many of the 
patients undergo prolonged operations with substantial blood loss.  These patients are 
somewhat coagulopathic immediately following surgery.  In addition, there is often a large 
potential dead space for the accumulation of a hematoma.  As a result, most surgeons 
do not use low molecular weight heparins or chemical anti-coagulation routinely following 
such operations.  The current standard of care is still TED hose and mechanical 
compression stockings. 
 
Dalteparin is a low-molecular weight heparin (LMWH) that has been shown to be effective 
as prophylaxis for deep venous thrombosis.8  It was the second LMWH approved by the 
FDA for this indication, and the medication has been used widely in orthopaedic patients, 
particularly those undergoing hip and knee replacement.  As a group, LMWHs are 
considered superior to unfractionated heparin in terms of bioavailability, longer half-lives, 
more predictable therapeutic response, and safety.9  In one meta-analysis of total hip 
arthroplasty, LMWHs were noted to result in significantly less major bleeding 
complications compared to unfractionated heparin.1  There are relatively few studies 
comparing dalteparin against other LMWHs such as enoxaparin, with regard to efficacy 
and bleeding complications.  In one retrospective study on prophylaxis in hip and knee 
replacement dalteparin appeared to have a slightly lower bleeding complication rate and 
comparable DVT rate.10  In another study, a prospective randomized trial was performed 
in patients with spinal cord injury.  There was no statistically significant difference in rates 
of DVT or bleeding complications.11  Similar findings were reported in another randomized 
trial in hip fracture patients.12   
 
In spite of surgeons’ concerns, it is reasonable to postulate that given the favorable safety 
profile of dalteparin, it can be used in this study population.  The key to using the 
medication would be to establish firm criteria for the safe use of the drug. 
 
The hypothesis is that the drug is safe for the patient population identified in this study.  
Most of the published safety data on the drug pertains to general orthopaedic patients 
and not to orthopaedic oncology patients.  This study is intended to provide preliminary 
data on benefits and risks for orthopaedic oncology patients. 
 
Orthopaedic oncology encompasses a wide array of patients.  Some patients are healthy 
and normal except for their tumor.  Other patients may be moribund with multiple co-
morbidities.  Some patients require a relatively small procedure to remove the tumor, 
while others require massive resections and reconstructions.  The risk of post-operative 
bleeding complications for these patients would be expected to vary considerably. 
 
As the first step toward establishing the use of dalteparin in orthopaedic oncology 
patients, it is proposed that two target populations be studied.  One group of patients is 
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comprised of those with metastatic disease in the lower extremity.  The other group of 
patients is composed of those who require major resection of sarcomas of the lower 
extremity. 
 
The two groups of patients are inherently different.  The patients with metastatic disease 
of the lower extremity are an important group since they encompass a large population 
of patients.  These patients are believed to be at the highest risk for DVT.  They tend to 
be older, more sedentary, less mobile, and have multiple c-morbid conditions.  These 
patients may be ideal candidates for treatments with dalteparin.  The patients typically 
undergo a limited excision or curettage followed by an intramedullary rod, plating, 
cementation, hip arthroplasty or knee arthroplasty.  The patients typically do not have 
much post-operative bleeding or drainage, since the skeletal defect is filled with bone 
cement.  There is typically no significant dead space after surgery in which a large 
hematoma or seroma could form. 
 
The patients with large primary sarcomas form a more challenging group.  These patients 
typically require major resections and reconstructions that could last 6 – 8 hours or more.  
The potential for intra-operative and post-operative bleeding is greater.  A larger, potential 
soft tissue cavity is often present after removal of large portions of muscles.  Post-
operative drainage through surgical drains often persists for 2 weeks or longer.  There is 
generally a much greater reluctance on the part of orthopaedic oncologist to treat such 
patients with low-molecular weight heparins. 
 
It is proposed that strict guidelines be established for the use of dalteparin in this second 
group of patients.  In the initial safety study, patients should be chosen that pose a 
moderate risk in terms of post-operative bleeding.  Patients who have extremely large 
tumors or those who become coagulopathic during surgery as a result of massive 
hemorrhage ought to be excluded.  Patients with superficial and small T1 (< 5 cm) tumors 
will also be excluded, since the soft tissue concerns are minimal in such patients.  The 
goal is to establish the safe use of dalteparin in the moderate risk group first.  This would 
become the starting point for a subsequent study on managing DVT risk in the patients 
at higher risk for complications. 
 
It is important to note that the underlying DVT rate in the pre-operative population is not 
well-established.  It is reasonable to hypothesize that there is a substantial rate of pre-
existing DVTs in patients with skeletal tumors.  However, there are currently no guidelines 
with regard to screening of such patients.  Pre-operative Doppler ultrasound examinations 
are not yet considered to be standard of care.  If a substantial rate of DVTs is found, then 
a compelling case may be made for not just pre-operative DVT screening, but also regular 
routine screening of cancer patients. 
 
It is well recognized that duplex Doppler ultrasound does not detect all DVTs.  It is most 
suited to detecting 95 – 100%.13  However, in well-controlled studies, the sensitivity is 
less, approximately 80%, and this may depend in part upon the experience of the 
ultrasonographer.  Venography is still considered superior in terms of sensitivity.  The 
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disadvantages of Venography include invasiveness, difficulty in studying patients with 
fractures, and a small risk of adverse reaction to intravenous dye.  The risk of a non-
invasive doppler ultrasound study is negligible.  The primary intent of the current safety 
study is to assess risk of prophylaxis with regard to bleeding complications in the wound 
as opposed to determining the absolute rate of DVT formation in the leg.  The safety and 
ease of duplex doppler ultrasound study make it suitable as the method for detecting 
DVTs in this study. 
 
This safety study is really part of an effort to develop a rational, comprehensive plan for 
management of DVT risk in a heterogeneous population of patients.  An important part of 
the management algorithm is screening for DVT in high risk groups.  Another important 
part of the management is developing different strategies for different types of patients.  
The initial phase of the study is geared towards establishing preliminary data on 
underlying rates of DVT, establishing the safe and effective use of dalteparin in certain 
patients with metastatic disease, and testing the safety of dalteparin in a subset of patients 
undergoing major sarcoma resections. 
 
Background Drug Information for Dalteparin14 
 
Use 
Prevention of deep vein thrombosis which may lead to pulmonary embolism, in patients 
requiring abdominal surgery who are at risk for thromboembolism complications (i.e., 
patients >40 years of age, obese, patients with malignancy, history of deep vein 
thrombosis or pulmonary embolism, and surgical procedures requiring general 
anesthesia and lasting longer than 30 minutes). 
 
Contraindications 
Hypersensitivity to dalteparin or any component of the formulation; thrombocytopenia 
associated with a positive in vitro test for antiplatelet antibodies in the presence of 
dalteparin; hypersensitivity to heparin or pork products; patients with active major 
bleeding; patients with unstable angina or non-Q-wave MI undergoing regional 
anesthesia; not for I.M. or I.V. use. 
 
Warnings/Precautions 
Patients with recent or anticipated neuraxial anesthesia (epidural or spinal anesthesia) 
are at risk of spinal or epidural hematoma and subsequent paralysis. 
 
Consider risk versus benefit prior to neuraxial anesthesia.  Risk is increased by 
concomitant agents which may alter hemostasis, as well as traumatic or repeated epidural 
or spinal puncture.  Patient should be observed closely for bleeding if dalteparin is 
administered during or immediately following diagnostic lumbar puncture, epidural 
anesthesia, or spinal anesthesia. 
 
Not to be used interchangeable (unit for unit) with heparin or any other low molecular 
weight heparins.  Use with caution in patients with known hypersensitivity to 
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methylparaben or propylparaben.  Use with caution in patients with history of heparin-
induced thrombocytopenia.  Monitor patient closely for signs or symptoms of bleeding.  
Certain patients are at increased risk of bleeding.  Risk factors include bacterial 
endocarditis; congenital or acquired bleeding disorders; active ulcerative or 
angiodysplastic GI diseases; severe uncontrolled hypertension; hemorrhagic stroke; or 
use shortly after brain, spinal, or ophthalmology surgery; in patients treated concomitantly 
with platelet inhibitors; recent GI bleeding; thrombocytopenia or platelet defects; severe 
liver disease; hypertensive or diabetic retinopathy; or in patients undergoing invasive 
procedures.  Use with caution in patients with severe renal failure (has not been studied).  
Safety and efficacy in pediatric patients have not been established.  Rare cases of 
thrombocytopenia with thrombosis have occurred.  Multidose vials contain benzyl alcohol 
and should not be used in pregnant women.  Heparin can cause hyperkalemia by affecting 
aldosterone.  Similar reactions could occur with LMWHs.  Monitor for hyperkalemia. 
 
Adverse Reactions 
 
1% to 10% 
 
 
 
 
 
Hematologic:  Bleeding (3% to 5%), wound hematoma (0.1% to 3%) 
 
 
 
Local:  Pain at injection site (up to 12%), injection site hematoma (0.2% to 7%) 
 
<1% (Limited to important or life-threatening): 
 
 
Thrombocytopenia 
(including 
heparin-induced 
thrombocytopenia), 
allergic 
reaction (fever, pruritus, rash, injections site reaction, bullous eruption), 
anaphylactoid reaction, operative site bleeding, gastrointestinal bleeding, skin 
necrosis.  Spinal or epidural hematomas can occur following neuraxial anesthesia 
or spinal puncture, resulting in paralysis.  Risk is increased in patients with 
indwelling epidural catheters or concomitant use of other drugs affecting 
hemostasis. 
 
Drug Interactions 
 
Drugs which affect platelet function (e.g., aspirin, NSAIDs, dipyridamole, ticlopidine, 
clopidogrel) may potentiate the risk of hemorrhage. 
 
Thrombolytic agents increase the risk hemorrhage. 
 
Warfarin:  Risk of bleeding may be increased during concurrent therapy.  Dalteparin is 
commonly continued during the initiation of warfarin therapy to assure anticoagulation 
and to protect against possible transient hypercoagulability. 
 
Ethanol/Nutrition/Herb Interactions 
 
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Herb/Nutraceutical:  Avoid cat’s claw, dong quai, evening primrose, garlic, ginseng (all 
have additional antiplatelet activity). 
 
Pharmacodynamics/Kinetics 
 
Onset of action:  1 – 2 hours 
 
Duration: >12 hours 
 
Half-life elimination (route dependent): 2 – 5 hours 
 
Time to peak, serum: 4 hours 
 
Dosage 
 
Adults:  SubQ: 2500 units 1 – 2 hours prior to surgery, then once daily for 5 – 10 days 
postoperatively. 
 
Monitoring Parameters 
 
Periodic CBC including platelet count; stool occult blood tests (if clinically indicated with 
signs of gastrointestinal bleeding such as melena, vomiting of coffee grounds, abdominal 
pain, sudden drop of hemoglobin); monitoring of PT and PTT is not necessary. 
 
Administration 
 
Administration once daily beginning prior to surgery and continuing 5 – 10 days after 
surgery prevents deep vein thrombosis in patients at risk for thromboembolic 
complications. 
 
Additional Information 
 
Molecular weight: 5000; sulfur content:  11% 
 
Dosage Forms 
 
Injection:  
 
Prefilled syringe:  Anti-Factor Xa 2500 units per 0.2 mL; Anti-Factor Xa 5000 units per 0.2 
mL 
 
Multidose vial:  95,000 units anti-Factor Xa/Vial (9.5 mL vial) = 10,000 units/mL 
 
Materials and Methods: 
 
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Patients 
 
There will be two study groups: 
 
Group A.  Metastatic disease in the lower extremity requiring limited excision (curettage) 
of tumor as part of surgical treatment.  Inclusion criteria would include all of the following: 
 
1. Metastatic disease, myeloma, or lymphoma. 
2. Pathologic fracture or impending pathologic fracture of the femur. 
3. Intramedullary rod, plating, cementation, hip arthroplasty or knee arthroplasty. 
 
Group B.  Primary sarcoma of the lower extremity requiring radical resection of tumor.  
Inclusion criteria would include all of the following: 
1. Primary sarcoma of bone or soft tissue of lower extremity. 
2. T2 tumor (> 5 cm but < 20 cm). 
3. Radical resection of tumor, which may necessitate major bone or soft tissue 
reconstruction. 
 
Exclusion criteria for both groups would include the following: 
 
1. Presence of DVT on pre-operative screening ultrasound study. 
2. Massive tumor (>20 cm in greatest dimension) 
3. Amputation of the affected leg as treatment for tumor. 
4. Estimated blood loss >2 liters during surgery. 
5. Surgical drain output >500 cc of bloody fluid during first 8 hours. 
6. I.N.R. >1.3 pre-operatively or > 1.5 post-operatively. 
7. Platelet count < 100,000 either pre-operatively or post-operatively. 
8. Indwelling post-operative epidural catheter for pain control. 
9. Age <30 years. 
10. History of underlying bleeding disorder, such as hemophilia. 
11. History 
of 
adverse 
reaction 
to 
heparin 
such 
as 
heparin-induced 
thrombocytopenia. 
12. Severe liver or renal insufficiency. 
13. History of hypertensive or diabetic retinopathy. 
14. History of gastro-intestinal bleeding within 12 months. 
15. Treatment with warfarin, clopidogrel, aspirin, NSAIDs, LMWH or other anti-
coagulants for conditions. 
16. History of stroke. 
17. Women of childbearing potential having a positive serum or urine pregnancy 
test (hCG) at the time of pre-operative evaluation (within 7 days of surgery). 
18. Women who are breast feeding. 
19. Hemoglobin < 8.0 gm/dl 
20. Platelet count < 100,000 /L 
21. Alanine aminotransferase >100 IU/L 
22. Aspartate aminotransferase > 100 IU/L 
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23. Direct bilirubin >0.5 gm/dL (the laboratory does not perform direct bilirubin if 
total bilirubin is below 0.2 mg/dl since direct bilirubin cannot be greater than 
total bilirubin). 
24. Serum creatinine > 2.0 gm/dL 
25. Patients taking COX-2 inhibitors. 
26. Patients who have fragmented mechanical heart valves. 
 
Study Design 
 
The study design will be an open-label, non-randomized clinical trial involving 25 – 35 
consecutive patients in each of the two groups.  Historical controls from this institution will 
be used to compare peri-operative bleeding events, drainage, transfusion requirements, 
and re-operation rates in similar patients who did not receive chemical prophylaxis for 
DVT.  Published historical controls will be used to compare the DVT rate.  The rate of 
DVT will be measured in this study, but the primary objective is to examine bleeding 
complications at the surgical site.  The sample size therefore is not calculated to establish 
efficacy, which has been demonstrated for patients in general in numerous previous 
articles. 
 
The study design will be an open-label, non-randomized clinical trial involving 25 – 35 
consecutive patients in each of the two groups.  To analyze wound complications 
historical controls will be identified through the Surgical Database maintained by the 
Section of Orthopaedics from this institution and will be used to compare peri-operative 
bleeding events, drainage, transfusion requirements, and re-operation rates in similar 
patients who did not receive chemical prophylaxis for DVT.  Data from surgery, including 
drain output, transfusion requirements, would complications, and re-operation for wound 
problems will be collected.  To analyze DVT rates and to compare against patients who 
did not receive, data from the previously published article by Lin et. al. will be used for the 
control group of patients with mechanical compression stockings alone.  Patients will 
receive a combination of dalteparin, bilateral TED hose, and bilateral mechanical 
compression stockings while in the hospital. 
 
Method of DVT Prophylaxis 
 
Patients will receive a combination of dalteparin, bilateral TED hose, and bilateral 
mechanical compression stockings while in the hospital. 
 
The reason for employing both mechanical prophylaxis and dalteparin together is as 
follows.  DVT prophylaxis is very difficult to achieve.  The DVT rate is never zero.  There 
is a very little, if any, adverse effects of using mechanical compression stockings. 
However, from the previous study at Memorial Sloan-Kettering, it is known that there is 
still a significant rate of DVT (17%) with mechanical prophylaxis.  Dalteparin and other 
low molecular weight heparins may improve upon this rate.  There is no contraindication 
to using both dalteparin and mechanical prophylaxis together.  The study is not intended 
to show that dalteparin obviates the need for mechanical prophylaxis.  
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Patients should not receive other anti-coagulants, such as aspirin, non-steroidal anti-
inflammatory drugs, and warfarin while on the study.  Heparin should not be administered 
except for routine intravenous catheter flushes. 
 
During surgery, patients will have TED hose and a mechanical compression stocking on 
the unaffected extremity.  For the operative leg TED hose and mechanical compression 
stocking will be applied in the recovery room. 
 
Patients will be mobilized out of bed with physical therapy as soon as deemed safe by 
the attending physician (generally post-operative day 1). 
 
Patients will not continue dalteparin after discharge from the hospital.  Patients are 
generally able to ambulate independently upon discharge, and are considered at reduced 
risk for DVT. 
 
Dosing of Dalteparin 
 
1. The unit dose will be 5000 units of dalteparin. 
2. The dosing will be once a day. 
3. The rouge of administration will be subcutaneous injection. 
4. The medication will start 12 – 24 hours after surgery on post-operative day #1. 
5. The medication will continue daily while the patient is in the hospital.  A follow-up 
doppler ultrasound study will be obtained prior to discharge (post-operative day 5 
– 14). 
 
Screening for DVT 
 
Each patient must have a pre-operative, bilateral doppler ultrasound study of the lower 
extremity veins, including the popliteal to the common femoral veins. 
 
Patients will receive a post-operative bilateral doppler ultrasound study of the operative 
limb prior to discharge home (generally post-operative day 5 – 14). 
 
The patients will be monitored by daily physical examinations while in the hospital.  Signs 
of acute DVT include pain, tenderness to deep palpation, swelling and a positive Homan’s 
sign.  Both legs will be monitored by examination.  Patients suspected of acute DVT will 
undergo emergent doppler ultrasound study.  Signs of pulmonary embolus (PE) include 
shortness of breath, pleuritic chest pain, dyspnea, hypoxia, and an arterial-alveolar 
oxygen gradient.  Patients suspected of acute PE will undergo emergent chest computed 
tomography and/or ventilation-perfusion lung scan. 
 
Endpoints of Analysis 
 
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1) Post-operative blood loss, as measured by the number of units of packed red 
blood cells transfused after surgery and change in hemoglobin levels. 
2) Post-operative drainage (cumulative) from surgical drains. 
3) Re-operation rate for post-operative complications, including hematomas, 
seromas, and infections. 
4) Rate of per-operative DVT in the study population. 
5) Rate of post-operative DVT in the lower extremities. 
6) Rate of clinically symptomatic pulmonary embolus. 
7) Bleeding at distant sites, such as the gastro-intestinal tract. 
 
Statistical Considerations 
 
The main purpose of this safety study is to evaluate the safety of dalteparin in patients 
undergoing orthopaedic oncologic procedures.  There is remarkably little information for 
the drug in patient population.  The main concern is that the drug could lead to increased 
bleeding, hematomas, seromas, and wound problems.  The safety study is intended to 
gather preliminary data that potentially could be used to formulate a larger study on DVT 
prophylaxis.  For the safety study, it seems reasonable to institute a stop rule.  The stop 
rule will terminate the study in case the drug leads to an unacceptable rate of adverse 
events.  The stop rules should not be based upon an arbitrary amount of post-operative 
drainage or weeks is a much better measure to use.  This is discrete event that is a 
common final outcome for unacceptable wound bleeding, large seromas and hematomas, 
and other wound problems. 
 
Two groups of patients will be evaluated in 2 independent cohorts, 1) patients who require 
major resection of sarcomas in the lower extremity, and 2) patients with metastatic 
disease of the lower extremity.  There is little information about safety and efficacy of 
dalteparin in these two patient groups.  Knowledge gained from the treatment of these 
patients will be used to design larger, more definitive studies.  Twenty-five patients will be 
treated in the metastatic cohort and 30 patients in the sarcoma cohort.  A total of 50 – 70 
patients will be accrued on this study. 
 
Safety Monitoring.  The primary endpoint for safety monitoring is the re-operation rate 
due to complications experienced by patients within the first 4 weeks after surgery.  In the 
sarcoma group, surgery can be extensive and clinical experience indicates that 
approximately 10% of patients will require re-operation within 4 weeks.15-17  A 25% re-
operation rate in this group of patients would be considered excessive.  For the metastatic 
patient group, the surgery is typically less involved and the re-operation rate during the 
first 4 weeks is near zero. 18 (we assume 3%) and a 15% re-operation rate would be 
considered excessive.  We will monitor this endpoint separately for these two patient 
groups using the sequential probability ratio test (Goldman 1987). 19 We assume a type 
1 error rate of 5% for both treatment groups.  Table 1 contains the stopping rules for each 
patient group.  For example, in the metastatic group, if 2 patients in the first 8 treated 
require re-operations to amend primary surgical complications, the protocol will stop 
accrual in this group.  Similar, if 4 of the first 8 patients in the sarcoma group require re-
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operation, accrual in this patient group will stop.  The probabilities of detecting excessive 
re-operation rates if the true rates are as high or higher than stated above using these 
two stopping rules are 6% and 72% for the metastatic and sarcoma patient groups, 
respectively. 
 
Table 1.  Stop trial for excessive re-operation rate if the number of re-operations at or 
larger than listed (No. Re-operations) are necessary in the number of patients 
treated. 
 
Metastatic Patients 
No. Re-operations 
2 
3 
4 
 
No. Patients 
8 
25 
25 
 
 
Sarcoma Patients 
No. Re-operations 
4 
5 
6 
7 
No. Patients 
8 
16 
26 
30 
 
Analysis Plan.  Several additional safety and efficacy endpoints will be estimated.  These 
include pre-operative DVT incidence, surgical drain output, the number of transfusions, 
post-operative DVT’s and others.  For continuous variables (e.g., surgical drainage, 
number of transfusions) data will be summarized using the mean (s.d.) and median 
(range).  For categorical variables (e.g., DVTs, gender) data will be summarized in 
frequency tables.  95% confidence intervals will be estimated for all outcomes.  For 
categorical outcomes, outcome estimates will be estimated with standard errors no larger 
than 9% and 10% for the sarcoma and metastatic patients, respectively. 
 
 
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Cost of Study 
The major cost of this study is the Doppler ultrasound test to detect lower extremity DVT’s.  
The cost is $475 per unilateral study and $950 per bilateral study at MD Anderson Cancer 
Center.  The medication will be provided by Pfizer.  The institutional tax is 25%, but this 
is waived for direct patient charges (i.e., ultrasound studies). 
 
Seventy patients are used as the basis for the cost analysis.  It is anticipated that there 
will be 50 patients on protocol in the study.  The cost estimate includes an additional 20 
patients for attrition from the study or exclusion from study as a result of a positive 
screening Doppler ultrasound test.  It is noted however that these patients do provide 
useful data and information that is part of the study.  If there is zero attrition and no pre-
operative DVTs, up to 10 additional patients will be included in each study group. 
 
Research Related 
Items 
Amount 
Overhead 
(25%) 
Notes 
Protocol Approval Fee 
$1,000  
n/c 
Required institutional fee for review and 
approval of clinical trials. 
PDMS User Fee 
$10,500 
$2,625  
Required institutional fee for registration 
in PDMS - $150/patient minimum. 
Experimental Pharmacy 
Fee 
$7,000  
$1,750 
Required institutional fee for experimental 
pharmacy handling/inventory control; 
$100/patient  
Diagnostic Imaging 
$96,250 
n/c 
Projected cost based on current rate.  
One bilateral Doppler ultrasound scan 
($950) + one unilateral scan ($475) per 
patient = $1375 per patient 
 
 
 
 
Administrative and 
miscellaneous costs  
$7,000 
$1,750 
$100/patient for unforeseen laboratory 
tests, document preparation, and non-
institutional overhead costs. 
 
 
 
 
Sub-total 
$121,750  
$6,125   
 
 
 
 
Total 
$127,875  
 
Direct cost per patient $1,739 
 
 
 
Indirect cost per patient $87.50 
 
 
 
Total cost per patient $1,827 
 
 
  
Revised 9/7/04 
 
  
 
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References 
 
1. 
Freedman KB, Brookenthal KR, Fitzgerald RH, Jr., Williams S, Lonner JH. A 
meta-analysis of thromboembolic prophylaxis following elective total hip 
arthroplasty. Journal of Bone & Joint Surgery - American Volume. 2000;82-
A(7):929-938. 
2. 
Westrich GH, Haas SB, Mosca P, Peterson M. Meta-analysis of thromboembolic 
prophylaxis after total knee arthroplasty.[see comment]. Journal of Bone & Joint 
Surgery - British Volume. 2000;82(6):795-800. 
3. 
Mandala M, Ferretti G, Cremonesi M, Cazzaniga M, Curigliano G, Barni S. 
Venous thromboembolism and cancer: new issues for an old topic. Critical 
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