Inferior vena cava filters in the management of cancer-associated venous thromboembolism: a systematic review

This study systematically reviews outcomes after inferior vena cava (IVC) filtration in cancer-associated venous thromboembolism (VTE). A comprehensive review of the English language literature was performed using MEDLINE, COCHRANE library, Embase and CINAHL on outcomes (i.e., pulmonary embolism, recurrent DVT, post-phlebitic syndrome and survival) following IVC filtration in cancer-associated VTE. Fourteen studies with 2,154 cancer patients receiving IVC filters post-VTE were included. All were observational studies. The mean duration of follow-up was 0.7–38 months and mean patient age was 56.8–68 years. Among study participants, 47–87% had stage 3 or 4 cancers. Of the 47–93% of filters inserted for contraindications to anticoagulation (AC), 10–33% were placed for relative contraindications. Recurrent PE was seen in 0–6%, fatal PE in 0–4.5%, recurrent DVT in 0–18.2%, post-phlebitic syndrome (PPS) in 0–2.7%, and IVC thrombosis (ICVT) in 3% of cancer patients. Median survival post-filter insertion was 2–10 months. Evidence supporting the utility of IVC filter insertion in cancer-associated VTE is limited to observational studies only. Preliminary data demonstrate similar safety and efficacy of filters in cancer and non-cancer populations. The combination of filters and anticoagulation is no more effective than either modality alone. Retrievable filters are an attractive option for prevention of VTE in the presence of temporary risk factors or temporary contraindications to anticoagulation in patients who have a reasonable life expectancy, but there is no evidence to support their preferential use in patients with advanced malignancy.     

Management of venous thromboembolism in patients with advanced cancer: a systematic review and meta-analysis

Venous thromboembolism is common in patients with cancer. However, no management guidelines exist for venous thromboembolism specific to patients with advanced progressive cancer. To help develop recommendations for practice, we have done a comprehensive review of anticoagulation treatment in patients with cancer, with particular focus on studies that included patients with advanced disease. Data from 19 publications, including randomised, prospective, and retrospective studies suggest that: long-term full-dose low-molecular-weight heparin (LMWH) is more effective than warfarin in the secondary prophylaxis of venous thromboembolism in patients with cancer of any stage, performance status, or prognosis; warfarin should not be used in patients with advancing progressive disease; and in patients at high risk of bleeding, full-dose LMWH for 7 days followed by a long-term decreased fixed dose long term can be considered. The optimum treatment duration is unclear, but because the prothrombotic tendency will persist in patients with advanced cancer, indefinite treatment is generally recommended. For patients with contraindications to anticoagulation, inferior-vena-caval filters can be considered, but their use needs careful patient selection. Ultimately, the decision to initiate, continue, and stop anticoagulation will need to be made on an individual basis, guided by the available evidence, the patient's circumstances, and their informed preferences.     

Anticoagulation for the initial treatment of venous thromboembolism in patients with cancer: a systematic review

BACKGROUND.

The authors compared the relative efficacy and safety of low‐ molecular‐weight heparin (LMWH) and unfractionated heparin (UFH) for the initial treatment of venous thromboembolism (VTE) between patients with and without cancer.

METHODS.

By using Cochrane methodology for systematic reviews, separate meta‐analyses were conducted for subgroups of patients with and without cancer, and relative risks (RRs) were compared for statistical significance. The methodologic quality for each outcome was assessed by using the Grading of Recommendations Assessment, Development, and Evaluation approach.

RESULTS.

LMWH reduced mortality significantly compared with UFH in patients with cancer (RR of 0.71; 95% confidence interval [95% CI], 0.52‐0.98 [moderate‐quality evidence]) but not in patients without cancer (RR of 0.97; 95% CI, 0.65‐1.46 [low‐quality evidence]). However, the difference in the RR for the 2 subgroups did not reach statistical significance (P = .113). The difference between LMWH and UFH in the effect on recurrent VTE was not statistically significant in the subgroup with cancer (RR of 0.78; 95% CI, 0.29‐2.08 [low‐quality evidence]), in the subgroup without cancer (RR of 0.94; 95% CI, 0.60‐1.46 [low‐quality evidence]), or between the 2 subgroups (P = .367). No data were available for bleeding outcomes, thrombocytopenia, or postphlebitic syndrome.

CONCLUSIONS.

The current results indicated that LMWH most likely is superior to UFH in reducing mortality in the initial treatment of VTE for patients with cancer. There is a need for more and better designed trials to confirm these findings. Cancer 2008. © 2008 American Cancer Society.     

Prevention and management of venous thromboembolism in people with cancer: a review of the evidence

Venous thromboembolism (VTE) constitutes an important health problem in developed countries. Owing to their underlying malignancies, people with cancer are at particularly high risk of VTE. The level of this risk is influenced by several factors, including type of cancer and the presence or absence of metastases. However, different types of oncology treatment can also further increase the thrombotic risk. Consequently, primary and secondary thromboprophylaxis in people with cancer should be considered as part of any integrated oncology treatment. Moreover, recent exciting studies have suggested that low molecular weight heparins (LMWH) may also influence overall survival in people with cancer. Clearly, these findings raise the likelihood that the use of LMWH in oncology practice may increase significantly in the near future. However, it is important to appreciate that the use of thromboprophylaxis in people with cancer is complicated by a number of specific problems. In this overview, we have systematically addressed the difficult clinical issues that are involved in the selection of appropriate primary and secondary thromboprophylaxis for people with cancer.     

Radiotherapeutic management of brain metastases: a systematic review and meta-analysis

BACKGROUND: The management of brain metastases is a significant health care problem. An estimated 20-40% of cancer patients will develop metastatic cancer to the brain during the course of their illness. METHODS: A systematic review of randomized trials on adult cancer patients with single or multiple brain metastases from cancer of any histology was conducted. Eligible studies investigated external beam radiotherapy or radiosurgery in one of the study arms. Outcomes of interest included survival, intracranial progression-free duration, response of brain metastases to therapy, quality of life, symptom control, neurological function, and toxicity. RESULTS: Twenty-seven trials were included in this systematic review of the evidence. Pooled results from three randomized trials of surgical excision combined with whole brain radiotherapy (WBRT) showed no improvement in overall survival as compared to WBRT alone in patients with single brain metastasis. One randomized study of postoperative WBRT following excision of a single brain metastasis versus surgery alone detected a significant reduction in intracranial tumour recurrence rates but no corresponding difference in overall survival. Nine trials of altered dose-fractionation schedules compared to a standard control fractionation schedule (3000 cGy in 10 fractions) of WBRT showed no difference in probability of survival at 6 months. The addition of radiosensitizers, as assessed in five trials, did not confer additional benefit to WBRT in terms of overall survival or the frequency of brain metastases response. Three trials examined the use of WBRT and radiosurgery boost versus WBRT alone in selected patients with brain metastases. Overall survival did not improve for patients with multiple brain metastases. However, one trial reported an improvement in survival for patients with single brain metastasis treated with WBRT and radiosurgery boost. One older randomized trial examined the use of WBRT versus supportive care alone (using oral prednisone). Results were not conclusive. CONCLUSION: For patients with a single brain metastasis, good performance status, and minimal or no evidence of extracranial disease, surgical excision and postoperative WBRT improves survival (as compared to WBRT alone). There may be a small survival advantage associated with the use of radiosurgery boost and WBRT as compared to WBRT alone in selected patients with a single brain metastasis. There is no difference in overall survival or in neurologic function improvement with the use of altered whole brain dose-fractionation schedules as compared to standard fractionation schedules (3000 cGy in 10 fractions or 2000 cGy in 5 fractions). There is no survival benefit associated with the use of radiosurgery boost and WBRT versus WBRT alone in patients with multiple brain metastases. Currently, neither chemotherapy nor radiosensitizers show a clear benefit in the objective parameters of survival and progression-free survival. For patients with poor performance status and active extracranial disease, steroids and supportive care are an option.     

Efficacy of clobazam as add-on therapy in brain tumor-related epilepsy

Journal of Neuro-Oncology - Brain tumor-related epilepsy (TRE) is often resistant to currently available antiepileptic medications (AEDs). Clobazam was initially approved as adjunctive AED for...     

Prophylaxis of venous thromboembolism in brain tumor patients

Summary Thromboembolism is a common problem in patients with brain tumors. Within this population are subpopulations of patients at varying but substantial risk for deep vein thrombosis and pulmonary embolism. Prophylactic strategies can be applied to these various risk groups that will dramatically reduce the incidence of thromboembolism, and these should be applied on a routine basis. The standard prophylactic methods for thromboembolic prophylaxis include mechanical devices (e.g., graduated leg stockings; external pneumatic calf compression) and pharmacological agents (e.g., low dose heparin). In addition, a basic knowledge of low molecular weight heparins and heparinoids is essential because these new agents have a potentially promising role in the prophylaxis of neurological disease in certain patients. The principles concerning the prophylaxis of venous thromboembolic disease in patients with brain tumors are addressed in this review.     

Endometrial cancer and venous thromboembolism in women under age 50 who take tamoxifen for prevention of breast cancer: a systematic review

Background

Breast cancer prevention with tamoxifen in high-risk women is limited due to concerns of endometrial cancer and thromboembolism. We report the risk of endometrial cancer, deep vein thrombosis and pulmonary embolism in women <50 years given tamoxifen for breast cancer prevention.

Methods

We searched the Cochrane Central Register of Controlled Trials and National Library of Medicine for published data from January 1970 to December 2010. We contacted principal investigators of clinical trials, and searched Grey literature and conference proceedings for unpublished data. We reviewed three breast cancer prevention trials comparing tamoxifen (20 mg per day) with placebo for five years in high-risk women <50 years. The absolute risk and relative risk (RR) for each outcome were estimated.

Results

The RR for endometrial cancer in women <50 years given tamoxifen is 1.19 (95% CI, 0.53–2.65; p = 0.6) as compared to the placebo. The RR for deep vein thrombosis with tamoxifen is 2.30 (95% CI, 1.23–4.31; p = 0.009) in the active phase of treatment. The risk decreases to 1.00 (95% CI, 0.38–2.67; p = 0.9) in the follow-up phase. The RR for pulmonary embolism with tamoxifen is 1.16 (95% CI, 0.55–2.43; p = 0.6).

Interpretation

The risk of endometrial cancer, deep vein thrombosis and pulmonary embolism is low in women <50 years who take tamoxifen for breast cancer prevention. The risk decreases from the active to follow-up phase of treatment. Education and counseling are the cornerstones of breast cancer chemoprevention.     

The role of steroids in the management of brain metastases: a systematic review and evidence-based clinical practice guideline

Question

Do steroids improve neurologic symptoms in patients with metastatic brain tumors compared to no treatment? If steroids are given, what dose should be used? Comparisons include: (1) steroid therapy versus none. (2) comparison of different doses of steroid therapy. Target population These recommendations apply to adults diagnosed with brain metastases. Recommendations Steroid therapy versus no steroid therapy Asymptomatic brain metastases patients without mass effect Insufficient evidence exists to make a treatment recommendation for this clinical scenario. Brain metastases patients with mild symptoms related to mass effect Level 3 Corticosteroids are recommended to provide temporary symptomatic relief of symptoms related to increased intracranial pressure and edema secondary to brain metastases. It is recommended for patients who are symptomatic from metastatic disease to the brain that a starting dose of 4–8 mg/day of dexamethasone be considered. Brain metastases patients with moderate to severe symptoms related to mass effect Level 3 Corticosteroids are recommended to provide temporary symptomatic relief of symptoms related to increased intracranial pressure and edema secondary to brain metastases. If patients exhibit severe symptoms consistent with increased intracranial pressure, it is recommended that higher doses such as 16 mg/day or more be considered. Choice of Steroid Level 3 If corticosteroids are given, dexamethasone is the best drug choice given the available evidence. Duration of Corticosteroid Administration Level 3 Corticosteroids, if given, should be tapered slowly over a 2 week time period, or longer in symptomatic patients, based upon an individualized treatment regimen and a full understanding of the long-term sequelae of corticosteroid therapy. Given the very limited number of studies (two) which met the eligibility criteria for the systematic review, these are the only recommendations that can be offered based on this methodology. Please see “Discussion” and “Summary” section for additional details.     

Patient- and tumor-related predictors of chemotherapy intolerance in older patients with cancer: A systematic review

Objective

The aim of this systematic review was to investigate patient-related factors (e.g. depressive symptoms, cognition, mobility, activities of daily living (ADL)) as well as tumor-related factors (e.g. tumor type, chemotherapy regimen) influencing chemotherapy intolerance in cancer patients aged 65?years or older.

Levetiracetam monotherapy in patients with brain tumor-related epilepsy: seizure control,safety, and quality of life

We performed a case series analysis to evaluate the effects of levetiracetam (LEV) monotherapy on seizures, adverse events, cognitive functioning and quality of life (QoL) in patients with brain tumor-related epilepsy (BTRE). We also explored the possible effects of systemic therapies on the efficacy of LEV. Twenty-nine patients were followed (13 female, 16 male; age 24–75 years) with 12 months of follow-up. Patients were evaluated by QoL and neuropsychological tests. At final follow-up, mean LEV dosage was 1991.4 mg/day. Among patients who reached the final follow-up of 12 months (n = 15), 1 patient had ≥50% reduction of seizure frequency (SF), and 14/15 were seizure free. The difference in presence/absence of seizures between baseline and final follow-up was significant (p < 0.001). Responder rate was 100%. We observed five side-effects: four mild (reversible) and one severe. Logistic regression revealed that chemotherapy and radiotherapy did not affect the efficacy of LEV in seizure outcome (p = 0.999). The following statistically significant observations emerged by tests’ evaluation: less worry about seizures, effects of antiepileptic, and ability to maintain social functions. Our data suggest that seizure occurrence can be an important warning sign that the clinician should heed throughout the duration of the illness. Patients with BTRE represent a unique patient population that presents difficulties regarding management of two very different pathologies: epilepsy on the one hand, and brain tumor on the other. Our data indicate that LEV, in patients with BTRE, is safe and efficacious, with positive impact on QoL.     

The role of prophylactic anticonvulsants in the management of brain metastases: a systematic review and evidence-based clinical practice guideline

Question

Do prophylactic anticonvulsants decrease the risk of seizure in patients with metastatic brain tumors compared with no treatment? Target population These recommendations apply to adults with solid brain metastases who have not experienced a seizure due to their metastatic brain disease. Recommendation Level 3 For adults with brain metastases who have not experienced a seizure due to their metastatic brain disease, routine prophylactic use of anticonvulsants is not recommended. Only a single underpowered randomized controlled trial (RCT), which did not detect a difference in seizure occurrence, provides evidence for decision-making purposes.     

Postoperative venous thromboembolism and brain tumors: part II. Hemostatic profile

Preoperative hemostatic data were obtained on 42 brain tumor patients and correlated with the subsequent occurrence of venous thrombosis detected with 1211-labeled fibrinogen leg scans. The occurrence of thrombosis correlated significantly with an increased prothrombin time, plasminogen, and total fibrinolytic activity and a decreased fibrinogen level. This overall trend in the group of patients with postoperative thrombosis indicates that the hemostatic disorder noted in brain tumor patients is most closely related to a subclinical form of chronic disseminated intravascular coagulation syndrome.Differences in hemostatic parameters seen with the various types of brain tumors suggest that biological factors specific to each tumor are likely responsible for the described hemostatic disorder and support the need for further research directed at the tumor tissue level.     

Postoperative venous thromboembolism and brain tumors: part I. Clinical profile

Forty-six patients who underwent surgery for brain tumors were studied prospectively with ¹²⁵I labeled Fibrinogen leg scans to detect postoperative venous thrombosis. The incidence of thrombosis was 72% for meningioma patients, 60% for glioblastoma patients, and 20% for brain metastasis patients.Correlation between the occurrence of venous thrombosis and the various clinical factors thought to be responsible for the high incidence of thrombosis generally failed to show statistical significance. This finding, along with the marked variation in the incidence of venous thrombosis between the different brain tumor groups, strongly suggests that biological factors play a more important role than clinical factors in determining which brain tumor patient will suffer a postoperative thrombosic event.     

Postoperative venous thromboembolism and brain tumors: part III. Biochemical profile

The plasminogen activator activity of 31 human brain tumor samples was assessed and the results correlated with clinical parameters and the postoperative occurrence of venous thrombosis. A significant negative correlation was found between plasminogen activator activity and venous thrombosis (P = 0.02), while positive correlations were observed between plasminogen activator activity and peritumoral brain edema (P = 0.03) and alpha₂ antiplasmin measured in the systemic circulation (P = 0.01). Tissue plasminogen activator was found in higher concentrations in meningioma tissue but did not correlate significantly with the occurrence of venous thrombosis. The results of this study suggest a local enzymatic degradation effect of plasminogen activator on thrombogenic substances present in the brain tumor and/or its environment.     

Low-molecular-weight heparins are superior to vitamin K antagonists for the long term treatment of venous thromboembolism in patients with cancer: a cochrane systematic review

Background

Cancer and its therapies increase the risk of venous thromboembolism. Compared to patients without cancer, patients with cancer anticoagulated for venous thromboembolism are more likely to develop recurrent thrombotic events and major bleeding. Addressing all important outcomes including harm is of great importance to make evidence based health care decisions. The objective of this study was to compare low molecular weight heparin (LMWH) and oral anticoagulants (vitamin K antagonist (VKA) and ximelagatran) for the long term treatment of venous thromboembolism in patients with cancer.

Methods

A systematic review of the medical literature. We followed the Cochrane Collaboration methodology for conducting systematic reviews. We assessed methodological quality for each outcome by grading the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology.

Results

Eight randomized controlled trials (RCTs) were eligible and reported data for patients with cancer. The quality of evidence was low for death and moderate for recurrent venous thromboembolism. LMWH, compared to VKA provided no statistically significant survival benefit (Hazard ratio (HR) = 0.96; 95% CI 0.81 to 1.14) but a statistically significant reduction in venous thromboembolism (HR = 0.47; 95% (Confidence Interval (CI) = 0.32 to 0.71). There was no statistically significant difference between LMWH and VKA in bleeding outcomes (RR = 0.91; 95% CI = 0.64 to 1.31) or thrombocytopenia (RR = 1.02; 95% CI = 0.60 to 1.74).

Conclusion

For the long term treatment of venous thromboembolism in patients with cancer, LMWH compared to VKA reduces venous thromboembolism but not death.     

Gemcitabine in the management of metastatic breast cancer: a systematic review

Background

A systematic review of the evidence for gemcitabine chemotherapy, alone or in combination, in women with metastatic/advanced breast cancer was undertaken in order to determine gemcitabine’s role in the first-line and/or second-line or greater setting.

Methods

MEDLINE, EMBASE, the American Society of Clinical Oncologists, San Antonio Breast Cancer Symposium proceedings, and the Cochrane Library were searched through September 2006 for randomized controlled trials and non-randomized phase two trials.

Results

Eighty-three trials were identified, including four randomized phase III trials. All of the phase III trials included first-line patients. Two of the phase III trails demonstrated clinical benefit with gemcitabine-based chemotherapy in terms of superior efficacy or less toxicity while two phase III trials found no clinical benefit based on less efficacy or increased toxicity. Although 78 phase II trials of gemcitabine alone or in combination with other chemotherapy agents were identified, few combinations showed results compelling enough to warrant randomized trials.

Conclusion

Available data do not support the acceptance of gemcitabine as a standard therapeutic option in women with metastatic breast cancer in the third-line or greater setting, nor should it be considered as first-line therapy in anthracycline naïve women. Gemcitabine appears to be most effective when administered with a taxane (docetaxel/paclitaxel) in the first- or second-line setting, with gemcitabine/taxane combinations representing a viable alternative to currently accepted taxane combinations such as capecitabine/docetaxel. There is no evidence at this time to support the use of gemcitabine triplets, given the equal efficacy to anthracycline triplets and the added toxicity.

     

The role of whole brain radiation therapy in the management of newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline

Should whole brain radiation therapy (WBRT) be used as the sole therapy in patients with newly-diagnosed, surgically accessible, single brain metastases, compared with WBRT plus surgical resection, and in what clinical settings?

Target population This recommendation applies to adults with newly diagnosed single brain metastases amenable to surgical resection; however, the recommendation does not apply to relatively radiosensitive tumors histologies (i.e., small cell lung cancer, leukemia, lymphoma, germ cell tumors and multiple myeloma). Recommendation Surgical resection plus WBRT versus WBRT alone Level 1 Class I evidence supports the use of surgical resection plus post-operative WBRT, as compared to WBRT alone, in patients with good performance status (functionally independent and spending less than 50% of time in bed) and limited extra-cranial disease. There is insufficient evidence to make a recommendation for patients with poor performance scores, advanced systemic disease, or multiple brain metastases. If WBRT is used, is there an optimal dosing/fractionation schedule? Target population This recommendation applies to adults with newly diagnosed brain metastases. Recommendation Level 1 Class I evidence suggests that altered dose/fractionation schedules of WBRT do not result in significant differences in median survival, local control or neurocognitive outcomes when compared with “standard” WBRT dose/fractionation. (i.e., 30 Gy in 10 fractions or a biologically effective dose (BED) of 39 Gy10). If WBRT is used, what impact does tumor histopathology have on treatment outcomes? Target population This recommendation applies to adults with newly diagnosed brain metastases. Recommendation Given the extremely limited data available, there is insufficient evidence to support the choice of any particular dose/fractionation regimen based on histopathology. The following question is fully addressed in the surgery guideline paper within this series by Kalkanis et al. Given that the recommendation resulting from the systematic review of the literature on this topic is also highly relevant to the discussion of the role of WBRT in the management of brain metastases, this recommendation has been included below. Does the addition of WBRT after surgical resection improve outcomes when compared with surgical resection alone? Target population This recommendation applies to adults with newly diagnosed single brain metastases amenable to surgical resection. Recommendation Surgical resection plus WBRT versus surgical resection alone Level 1 Surgical resection followed by WBRT represents a superior treatment modality, in terms of improving tumor control at the original site of the metastasis and in the brain overall, when compared to surgical resection alone.     

The role of chemotherapy in the management of newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline

Target population

This recommendation applies to adults with newly diagnosed brain metastases; however, the recommendation below does not apply to the exquisitely chemosensitive tumors, such as germinomas metastatic to the brain.

Recommendation

Should patients with brain metastases receive chemotherapy in addition to whole brain radiotherapy (WBRT)? Level 1 Routine use of chemotherapy following WBRT for brain metastases has not been shown to increase survival and is not recommended. Four class I studies examined the role of carboplatin, chloroethylnitrosoureas, tegafur and temozolomide, and all resulted in no survival benefit. Two caveats are provided in order to allow the treating physician to individualize decision-making: First, the majority of the data are limited to non small cell lung (NSCLC) and breast cancer; therefore, in other tumor histologies, the possibility of clinical benefit cannot be absolutely ruled out. Second, the addition of chemotherapy to WBRT improved response rates in some, but not all trials; response rate was not the primary endpoint in most of these trials and end-point assessment was non-centralized, non-blinded, and post-hoc. Enrollment in chemotherapy-related clinical trials is encouraged.