Kirk J. Matthews
History of present illness
A 62-year-old postmenopausal white woman, who is currently being treated for stage IIa ovarian adenocarcinoma, presents to the emergency department with severe pain in the right side of her pelvis that radiates down into her right lower extremity.
Her symptoms started one day prior and are constant in nature. She reports no alleviating or exacerbating factors. She has a small amount of associated lower extremity swelling and denies any trauma to the affected area.
Her ovarian adenocarcinoma was treated with an initial staging procedure consisting of a total abdominal hysterec- tomy, bilateral salpingo-oophrectomy, omentectomy, and pelvic and para-aortic lymph-node dissection approximately four months ago. She finished her second cycle of adjuvant chemotherapy, with carboplatinum and taxol, two weeks ago.
She has tolerated these treatments well with the exception of nausea and vomiting, which are well managed with ondansetron.
The patient’s past medical history is otherwise benign. She is a gravida 3, para 3 woman who has been postmenopausal for 10 years. She denies previous sexually transmitted infec- tions or abnormal cervical screening. Her family history is notable for adult-onset diabetes mellitus. She denies tobacco use and reports drinking two to three glasses of wine per week. She is a retired accountant who has been married for 35 years.
Physical examination
General appearance:Well-developed, well-groomed woman who appears anxious and unable to get comfortable on the hospital bed
Vital signs:
Temperature: 37.9°C Pulse: 106 beats/min
Blood pressure: 135/88 mmHg Respiratory rate: 18 breaths/min Oxygen saturation: 96% on room air BMI: 36 kg/m2
Weight: 198 lb
HEENT:Moist mucous membranes; no jugular venous distention or carotid bruit appreciated
Chest:Lungs are clear to auscultation
Cardiac:Examination reveals a mild sinus tachycardia Abdomen:Soft, no abnormal masses, nontender,
nondistended. A midline vertical surgical incision appears well healed and without signs of infection
Lymphatics:No lymphadenopathy noted in the bilateral groins
External genitalia/vagina:Unremarkable with no discharge or bleeding noted; normal appearing vaginal mucosa;
well-healed vaginal cuff
Extremities:+1 Edema noted in the right lower extremity to the upper calf. Tenderness in the right calf noted with palpation. The pain is exacerbated by dorsiflexion of the patient’s foot
Laboratory studies:
WBCs: 6000/μL (normal 4000–12 000/μL) Hb: 9.8 g/dL (normal 12.0–15.0)
Platelets: 215 000/μL (normal 172 000–440 000/μL) Electrolytes are within normal limits
Urinalysis reveals no evidence of infection
How would you manage this patient?
Given this patients symptoms in the setting of ongoing treat- ment for an ovarian malignancy, a deep venous thrombosis (DVT) should be high on the differential diagnosis and requires further assessment. DVTs may present with a wide range of clinical signs and symptoms including pain, erythema, unilateral swelling, or warmth of the affected extremity. The history and medical context should raise suspicion for a DVT, which requires diagnostic confirmation.
Doppler ultrasonography of the right lower extremity was performed and was found to be positive for a large DVT in the right popliteal vein. The patient was promptly started on low- molecular-weight heparin (LMWH) and she was admitted to the hospital for initial monitoring. After initiating LMWH anticoagulation at 90 mg subcutaneously every 12 hours, she was also started on an oral vitamin K antagonist (warfarin), which was titrated until an international normalized ratio (INR) was in the therapeutic range of 2.0–3.0. The patient felt she was able to comply with oral therapy better than subcuta- neous injections for her follow-up. Her anticoagulation treat- ment will be continued for a minimum of six months while she continues her chemotherapy.
Acute Care and Emergency Gynecology, ed. David Chelmow, Christine R. Isaacs and Ashley Carroll. Published by Cambridge University Press.
© Cambridge University Press 2015.
Venous thromboembolism in cancer patients
There are numerous environmental, inherited, and acquired risk factors that influence a hypercoaguable state. Chief among these, however, are patients with an active malignancy.
Venous thromboembolism (VTE) includes both deep venous thrombosis (DVT) and pulmonary embolism (PE) and is a major complication of cancer, occurring in anywhere from 4 to 20% of patients. Hospitalized patients with cancer and those receiving active therapy seem to be at the greatest risk for development of VTE. In a population-based study, cancer was associated with a 4.1-fold greater risk of thrombosis, whereas the use of chemotherapy increased the risk 6.5-fold [1].
Increasing the risk for VTE formation amongst patients with malignancy include higher stages of cancer at time of diagnosis, intervals less than six months since the time of diagnosis (as in the case of this patient), current treatment with chemotherapeutic agents or radiation, and indwelling venous access catheters [1].
Symptoms that commonly arise during DVT formation are swelling of the affected extremity, pain or tenderness (oftentimes only felt when provoked with standing or walking), increased warmth in the area of the extremity that is swollen or painful, and erythema or discoloration of the skin on the affected extremity. A common physical examination finding as was found in our patient is that of Homan’s sign.
A positive Homan’s sign occurs when there is pain elicited in the calf on dorsiflexion of the patient’s foot at the ankle joint while the knee is fully extended.
When clinical suspicion for a DVT exists, radiologic confirmation is required to make the diagnosis. Historically, CT contrast venography was the“gold standard”for confirming the diagnosis of a DVT. Unless a DVT needs to be identified deep within the pelvis however, today it is rarely used as veno- graphy is invasive, expensive, and has been shown to cause thrombosis on its own. By contrast, Doppler ultrasonography is noninvasive, inexpensive and typically readily available. Dop- pler ultrasound is the diagnostic test of choice with a mean sensitivity and specificity for the diagnosis of symptomatic proximal DVT at 97% and 94%, respectively. Laboratory assess- ment with D-dimer levels should not be obtained as patients with cancer will often have an elevated D-dimer even in the absence of a VTE. Using D-dimer levels may be helpful in excluding VTE in patients with a low pretest probability, but it certainly would not be useful in the case of this patient given the context of her malignancy and current chemotherapy treatment.
According to the American Society of Clinical Oncology (ASCO), 2013 guideline updates for VTE prophylaxis and treatment, treatment with LMWH is preferred over unfractio- nated heparin (UFH) for the initial 5–10 days of anticoagula- tion for the cancer patient with a newly diagnosed VTE (as long as no renal impairment exists defined as creatinine clearance
<30 mL/min) [2]. These recommendations are due in part to a recent Cochrane meta-analysis, which found improved survival rates in cancer patients who were treated with LMWH over
UFH [3]. Dosing should be weight-based for treatment (Table 95.1) and can be administered as a twice-daily or once- daily regimen [2].
The 2013 ASCO guidelines recommend treatment regi- mens should be continued for a period of at least six months in the oncology patient with a VTE [2]. For this treatment duration, LMWH is still preferred over vitamin K antagonists (warfarin) due to improved efficacy and ease of administration.
In addition, LMWH carries the added benefit of not requiring any laboratory monitoring to follow clotting factor levels such as prothrombin time (PT), INR, or factor Xa levels. In con- trast, however, vitamin K antagonists are much less costly, can be administered orally, and are an acceptable alternative for long-term therapy if LMWH is not feasible. If vitamin K antagonists are chosen for long-term use, they should be started while the patient is being treated concurrently with LMWH as “bridge therapy”until an INR of 2–3 is achieved.
In the outpatient setting, INRs must be also checked frequently to ensure adequate dosing, and the practitioner must be mindful of other medications and dietary influences that may interact with vitamin K antagonists and, thus, alter INR levels.
At this time, no published studies address the need for further treatment of VTE beyond six months. However,
Table 95.1Dosing regimens for treatment of VTE in patients with cancer
Treatment of established DVT Clinical
setting
Drug Regimen*
Initial
UFH 80 U/kg IV bolus, then 18 U/kg per hour IV. Adjust dose based on aPTT Dalteparin 100 U/kg once every 12 hours or
200 U/kg once daily
Enoxaparin 1 mg/kg once every 12 hours or 1.5 mg/kg once daily
Tinzaparin 175 U/kg once per day Fondaparinux <50 kg, 5.0 mg once daily
50–100 kg, 7.5 mg once daily
>100 kg, 10 mg once daily Long-term
Dalteparin 200 U/kg once daily for 1 month, then 150 U/kg once daily Enoxaparin 1.5 mg/kg once daily or 1 mg/kg
once every 12 hours Tinzaparin 175 U/kg once daily
Warfarin Adjust dose to maintain INR 2–3
* All doses are given as subcutaneous doses except as indicated.
aPTT, activated partial thromboplastin time; DVT, deep venous thrombosis;
INR, international normalized ratio; IV, intravenous; UFH, unfractionated heparin; VTE, venous thromboembolism.
certain experts agree that continuing anticoagulation beyond six months should be considered for selected patients who continue to have high-risk factors for recurrent VTEs. This decision must be balanced against the inherent risk of bleeding while on anticoagulation, costs, and patient compliance [2].
Contraindications to therapeutic anticoagulation include severe platelet dysfunction, active peptic or other gastrointest- inal ulceration at risk of bleeding, major surgery or serious bleeding within the preceding 2 weeks, or persistent thrombo- cytopenia (platelets<50 000/μL). In these instances, the inser- tion of a vena cava filter is often indicated. Vena cava filters may also be considered as additional therapy in patients with progression of thrombosis despite treatment therapy with LMWH or warfarin.
Since cancer patients have such a dramatic overall increased risk of VTE formation, questions often arise as to whether VTE prophylaxis is indicated in this population. For this reason, ASCO recommends that hospitalized patients who have an active malignancy with an acute medical illness or reduced mobility should receive pharmacologic thromboprophylaxis, assuming no active bleeding is observed. As with treatment- dosing regimens, there are several regimens available for prophylaxis dosing (Table 95.2). For active, ambulatory cancer patients not admitted to the hospital, current recommendations do not include routine pharmacologic thromboprophylaxis in patients who are undergoing short chemotherapy infusions in the outpatient setting. Anticoagulants are not recommended to improve survival in cancer patients without a VTE [1].
Over the years, there have been several attempts to con- struct predictive models to aid in the identification of cancer patients who are at heightened risk for the development of VTE in the outpatient setting. The risks versus benefits of medical thromboprophylaxis in such patients are still being studied and as such, routine thromoboprophylaxis is not cur- rently recommended.
Key teaching points
Clinicians should have high suspicion for deep venous thrombosis (DVT) in an oncology patient presenting with any new-onset symptoms of unilateral lower extremity pain, erythema, swelling, or tenderness.
A D-dimer is not a helpful diagnostic laboratory value in the cancer patient.
Doppler ultrasound is the diagnostic test of choice with high sensitivity and specificity for diagnosing a DVT.
Treatment for a DVT in the cancer patient should begin with low-molecular-weight heparin, ideally for a minimum of six months. Other treatment regimens can be
considered.
While the cancer patient is considered high risk for development of a VTE, current recommendations do include thromboprophylactic therapy for an ambulatory patient in the outpatient setting.
References
1. American Society of Clinical Oncology.
Recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer:
practice guideline.Jour Clin Oncol 2007;25:5490–505.
2. American Society of Clinical Oncology.
Venous thromboembolism prophylaxis and treatment in patients with cancer:
practice guideline update.Jour Clin Oncol2013;31:2189–204.
3. Akl EA, Vasireddi SR,Gunukula S, et al.
Anticoagulation for the initial
treatment of venous thromboembolism in patients with cancer.Cochrane Database Syst Rev2011, Issue 2.
Art. No.: CD006649. DOI: 10.1002/
14651858.
Table 95.2 Dosing regimens for prophylaxis of VTE in patients with cancer
Prophlaxis of VTE Clinical
setting
Drug Regimen*
Hospitalized
UFH 5000 U once every 8 hours Dalteparin 5000 U once daily Enoxaparin 40 mg once daily Fondaparinux 2.5 mg once daily Surgical patients
UFH 5000 U 2–4 hours preop. and then once every 8 hours thereafter
Dalteparin 2500 U 2–4 hours preop. and then once daily thereafter Enoxaparin 20 mg 2–4 hours preop. and
40 mg once daily thereafter Fondaparinux 2.5 mg once daily beginning
6–8 hours postop.
* All doses are given as subcutaneous doses except as indicated.
UFH, unfractionated heparin; VTE, venous thromboembolism.
Case 95: A 62-year-old woman with ovarian cancer and new-onset pelvic and right-leg pain