Cancer.pdf

guideline

Guideline on aspects of cancer-related venous thrombosis Henry G. Watson,1 David M. Keeling,2 Mike Laffan,3 Robert Campbell Tait,4 and Mike Makris5,6 on behalf of the British Committee for Standards in Haematology 1

Department of Haematology, Aberdeen Royal Infirmary, Aberdeen, 2Oxford Haemophilia & Thrombosis Centre, Churchill Hospital, Oxford, 3Centre for Haematology, Imperial College, Hammersmith Hospital, London, 4Department of Haematology, Glasgow Royal Infirmary, Glasgow, 5Sheffield Haemophilia and Thrombosis Centre, and 6Department of Cardiovascular Science, University of Sheffield, Sheffield, UK

Summary The guideline was drafted by a writing group identified by the Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology (BCSH). All the authors are consultants in haematology in the UK. A search was performed of PubMed and Embase using the term ‘cancer’ combined with ‘thrombosis’, ‘treatment’, ‘prophylaxis’ and ‘clinical presentation’. The search covered articles published up until December 2014. Only human studies were included and articles not written in English were excluded. References in recent reviews were also examined. The writing group produced the draft guideline, which was subsequently revised by consensus by members of the Haemostasis and Thrombosis Task Force of the BCSH and the BCSH executive. The guideline was then reviewed by the sounding board of the British Society for Haematology (BSH). This comprises 50 or more members of the BSH who have reviewed the guidance and commented on the content and application to the UK setting. The ‘GRADE’ system was used to quote levels and grades of evidence, details of which can be found at: http://www.bcshguidelines.com/ BCSH_PROCESS/EVIDENCE_LEVELS_AND_GRADES_OF_ RECOMMENDATION/43_GRADE.html. The objective of this guideline is to provide healthcare professionals with clear guidance on the prevention and management of venous thromboembolism (VTE) in patients with cancer and to advise on an approach to screening for cancer in patients with unprovoked VTE in whom cancer was not initially suspected based on clinical grounds. Keywords: cancer, clinical aspects, venous thrombosis, anticoagulation. The association between cancer and thrombosis is well established. There are several mechanisms that may explain why cancer increases the propensity to develop venous thrombo-

Correspondence: BCSH secretary, British Society for Haematology, 100 White Lion Street, London N1 9PF, UK. E-mail [email protected]

First published online 26 June 2015 doi: 10.1111/bjh.13556

embolism (VTE). Less well understood are the mechanisms behind the increased risk of developing cancer at times far removed, often years after thrombosis, that has been described in large population studies (Baron et al, 1998). It is likely that this reflects shared risk factors for development of both cancer and thrombosis such as, for example, smoking and obesity. The expression of tissue factor on tumour cells and the prothrombotic properties of mucins contribute to the thrombosis risk in malignancy. In addition there is evidence that tissue factor expression, which may result from proto-oncogene expression and tumour suppressor gene inhibition, confers a pro-angiogenic state, which may enhance the aggressiveness and invasiveness of cancers. Malignancy itself, surgery, indwelling intravenous catheters, chemo-radiotherapy and intercurrent medical complications, such as infection, all contribute to the increased risk of thrombosis in cancer patients. Thrombotic events rank second only to the direct effects of cancer as a cause of death in cancer patients (Khorana, 2010). Several studies have assessed differences in the risk of thrombosis between cancers. Several tumour sites, including lung, brain, pancreas, stomach, ovary and kidney, and also lymphoma have the strongest reported association with thrombosis development (Agnelli, 1997; Baron et al, 1998). Most studies confirm that the development of VTE in patients with cancer is associated with a poorer prognosis than that seen in thrombosis-free cancer patients and this was confirmed in all 12 tumour types in one study (Chew et al, 2006). Whether this is related to the effects of thrombosis or reflects inherent tumour aggressiveness is not clear. It has also been observed that cancer patients with VTE have poorer outcomes as judged by the need for hospital admission, higher rates of major bleeding and higher rates of thrombosis recurrence on anticoagulant therapy compared with patients who do not have cancer (Levitan et al, 1999; Palareti et al, 2000; Prandoni et al, 2002; Trujillo-Santos et al, 2008).

Thromboprophylaxis and cancer Since 2007, it has been routine care to perform a risk assessment for thrombosis on all hospitalized patients in the UK ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 170, 640–648

Guideline (Department of Health, 2007; National Institute for Health and Clinical Excellence (NICE) 2010). In practice, patients with active cancer admitted for medical or surgical reasons, should be offered pharmacological thromboprophylaxis except where the likely benefit is outweighed by the associated bleeding risk (Kahn et al, 2012). For these purposes active cancer should be considered to include a diagnosis of cancer, other than basal cell or squamous cell carcinoma of the skin, within the previous 6-month period, and any treatment for cancer within the previous 6-month period or recurrent or metastatic cancer (Lee et al, 2003). A number of studies have investigated the use of routine thromboprophylaxis in ambulatory cancer outpatients receiving chemotherapy. A Cochrane review of 9 randomized controlled trials (RCTs) involving 3538 patients, which compared patients receiving thromboprophylaxis [eight low molecular weight heparin (LMWH) and one warfarin] with control groups, found a reduction in VTE risk [relative risk (RR) 0
66 (0
41–0
93)] without a significant increased risk of bleeding [RR 1
57 (0
69–3
6)] (Di Nisio et al, 2012). However, this analysis identified that 60 patients needed to be treated to prevent 1 episode of thrombosis, suggesting that thromboprophylaxis should not be used routinely in outpatients with cancer but should be considered in individuals at very high thrombotic risk. Identification of these high risk patients can be aided by the use of risk assessment scores, such as that developed by Khorana et al (2008) (Table I) which identifies as higher risk patients with stomach, pancreas, lung, gynaecological, bladder or testicular cancer or lymphoma as well as the presence of a platelet count

>350 9 109/l, haemoglobin concentration <100 g/l, leucocyte count pre-chemotherapy >11 9 109/l and a body mass index of >35 kg/m2 (Khorana et al, 2008). Alternatively, an international practice guideline, whilst also not recommending routine prophylaxis, suggests consideration in patients with locally advanced or metastatic pancreatic and lung cancer who are not deemed at excessive risk for bleeding (Farge et al, 2013). There is a well-recognized association between multiple myeloma and VTE, which is further increased in patients treated with thalidomide or lenalidomide. The role of thromboprophylaxis in this setting has been reviewed recently in two BCSH guidelines, which recommend risk assessment and treatment with low dose aspirin if low risk and LMWH or dose-adjusted warfarin if non-low risk. Thromboprophylaxis should be continued until disease control is achieved (Bird et al, 2011; Snowden et al, 2011). The role of the new oral anticoagulants dabigatran, rivaroxaban, apixaban and edoxaban as prophylaxis in cancer patients has not yet been determined.

Surgical prophylaxis Recently, a move towards extended prophylaxis for high-risk surgical patients, such as those requiring surgery for the management of abdominal and pelvic cancer, has developed. This treatment should be considered for certain groups of patients (NICE, 2010).

Recommendations Table I. Predictive model thromboembolism.

for

chemotherapy-associated

Patient characteristic

venous

Risk score

Site of cancer Very high risk (stomach, pancreas) High risk (lung, lymphoma, gynaecological, bladder, testicular) Pre-chemotherapeutic platelet count ≥350 9 109/l Haemoglobin concentration <100 g/l or use of erythropoiesis-stimulating agents Pre-chemotherapeutic leucocyte count >11 9 109/l Body mass index ≥ 35 kg/m2

2 1 1 1 1 1

Thrombosis rate per 2
5 months (%) Low score Intermediate score High score

0 1–2 >2

0
3–0
8 1
8–2 6
7–7
1

This table has been modified from research originally published in Blood. Khorana, A.A., Kuderer, N.M., Culakova, E., Lyman, G.H. & Francis, C.W. (2008) Development and validation of a predictive model for chemotherapy associated thrombosis. Blood, 111, 4902– 4907. © the American Society of Hematology. ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 170, 640–648

 Patients with active or recent cancer admitted to hospital should receive thromboprophylaxis throughout their admission unless contraindicated (2C).  Patients undergoing abdominal and pelvic surgery for cancer should be considered for extended thromboprophylaxis (2B).  Outpatients with active cancer should be assessed for thrombosis risk and although most do not routinely require thromboprophylaxis, it should be considered for high risk patients (2B).  Patients with myeloma receiving thalidomide or lenalidomide should be risk-assessed for VTE and offered thromboprophylaxis unless there is a contraindication (1A).  Thromboprophylaxis should be reviewed in patients with thrombocytopenia. A platelet count of <50 3 109/l is a relative contraindication to pharmacological prophylaxis (1C).

Prevention of catheter-related thrombosis A prospective study of 82 patients reported that fixed, low dose warfarin was very effective in reducing the risk of 641

Guideline catheter-related thrombosis (Bern et al, 1990). More recently, however, the WARP (Warfarin thromboprophylaxis in cancer patients with central venous catheters) trial, which randomized 812 patients to warfarin or no therapy found no difference in the risk of catheter-related thrombosis between the two groups (Young et al, 2009). A Cochrane review evaluated the efficacy of oral and parenteral anticoagulants in the prevention of central venous catheter-related thrombosis reported up to February 2010. Neither warfarin nor prophylactic dose LMWH was associated with reduction in risk (Akl et al, 2011a).

major bleeding, there was no effect on survival (Akl et al, 2011b). The second Cochrane review published in 2011 examined studies comparing periods of unfractionated heparin (one study) or LMWH (eight studies) at different doses and for different periods of time versus placebo or no treatment (Akl et al, 2011c). A survival benefit was observed at 24 months but not at 12 months, accompanied by a significant reduction in VTE without an increase in bleeding (Akl et al, 2011c). More recently, no difference in survival was found in an RCT of patients with advanced malignancy that compared LMWH with placebo (van Doormaal et al, 2011a).

Recommendation

Recommendation

 Routine use of anticoagulants at prophylactic or therapeutic dose to prevent catheter-related thrombosis in cancer patients is not recommended (1A).

 Antithrombotic use aimed solely at increasing life expectancy in patients with cancer but without a history of VTE, is not recommended (1A).

Thromboprophylaxis in patients on long-term prothrombotic anti-cancer therapies Some patients will have no evidence of active malignant disease but benefit from long term adjuvant treatment with agents such as tamoxifen. In the large (16 289 women) Danish registry of women taking tamoxifen after treatment for breast cancer, the 5-year incidence of VTE was 1
2% vs. 0
5% for those not taking tamoxifen, with the highest risk of thrombosis in older women and in the first 2 years of treatment [RR 3
5; 95% confidence interval (CI) 2
1–6
0] (Hernandez et al, 2009). Although the RR is elevated, the absolute risk is not sufficiently high to warrant concomitant prophylactic anticoagulation. A systematic review of adjuvant hormone therapies produced similar conclusions (Deitcher & Gomes, 2004). In women who have had cancer-associated thrombosis and who require longer term treatment with tamoxifen, it may be reasonable to continue with anticoagulation for the duration of the adjuvant therapy.

Recommendation  Patients without a history of VTE receiving adjuvant hormonal therapies for cancer should not routinely receive thromboprophylaxis (1B).

Anticoagulants and thromboprophylaxis to prolong cancer survival Some early observations suggested that antithrombotic drugs may prolong survival in cancer patients. Two Cochrane systematic reviews have been published in the area. The first (Akl et al, 2011b) evaluated the evidence comparing oral anticoagulants, at a variety of intensities with no treatment or prophylactic treatment. Although warfarin reduced the incidence of VTE at the expense of higher rates of minor and 642

Treatment of symptomatic cancer-associated VTE Initial treatment (up to 6 months) Patients with cancer-associated VTE have a higher risk of recurrence on treatment than those without cancer (Prandoni et al, 2002). The CLOT trial (Lee et al, 2003) demonstrated that treatment of cancer-associated VTE with 6 months of LMWH resulted in a significantly lower recurrence rate at 6 months than conventional treatment with International Normalized Ratio-adjusted warfarin [7
9% vs. 15%, Hazard ratio (HR) = 0
48; 95% CI, 0
30–0
77]. The superiority of continued LMWH treatment over LMWH followed by a vitamin K antagonist (VKA) is supported by two other studies (Meyer et al, 2002; Hull et al, 2006). In the CLOT study full dose dalteparin was given for 1 month followed by a reduced dose (75–80%) for months 2–6 (Lee et al, 2003). In the other two studies full dose tinzaparin or enoxaparin was given for 3 months (Meyer et al, 2002; Hull et al, 2006). None of the studies showed any excess of bleeding associated with continued LMWH. There are no direct comparisons of 3 months vs. 6 months of treatment. Problems associated with the use of warfarin, such as numerous drug interactions, the effect of diet, oral route of administration and slow onset and offset of action, make it difficult or unsuitable for the management of patients with malignancy. On the other hand, possible barriers to LWMH use are the need for subcutaneous injection and impaired renal function. Therapeutic dose LMWH should be used with some caution in patients with renal impairment and dose reduction or anti-Xa monitoring may be indicated in patients with estimated creatinine clearance <30 ml/min or very low body weight. Unfractionated heparin can be used for initial treatment, but is not practical for prolonged outpatient therapy. We suggest warfarin for maintenance in this circumstance. ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 170, 640–648

Guideline The trials of dabigatran, rivaroxaban, apixaban and edoxaban or directly acting oral anticoagulants (DOACs) for treatment of VTE contained only small numbers of patients with cancer. Subgroup analysis suggests they may have similar efficacy to warfarin but no comparison with LMWH has been made (van der Hulle et al, 2014). The DOACs have many of the logistical advantages of LMWH in these patients undergoing active treatment. For patients who cannot have or tolerate subcutaneous LMWH we suggest warfarin or a DOAC.

Thrombosis recurrence during treatment Thrombosis recurrence during treatment is reported in 6–9% of cancer-associated VTE patients receiving LMWH and 10– 17% of those receiving warfarin (Lee, 2012). There is limited evidence regarding the management of recurrence of thrombosis in patients with cancer on active anticoagulant treatment. Recurrence in patients taking warfarin should be managed by switching to LWMH. Those patients using LMWH at approximately 75% of the normal therapeutic dose, which is usual practice after the first month of treatment, should increase to the full weight-based therapeutic dose. For those already receiving full dose LMWH, there is some evidence to support further increasing the dose of LMWH by 20–25% (Carrier et al, 2009). If there is continued evidence of clot extension, then an option is to increase the LMWH dose guided by anti-Xa measurement. A suggested regimen is to aim for a peak anti-Xa level of 1
6– 2
0 u/ml for once daily LMWH and 0
8–1
0 u/ml peak for twice daily treatment (Carrier et al, 2009, 2013; Lee, 2012). The benefit of dividing higher doses is uncertain but in the only comparative trial, there was a trend in the cancer subgroup for lower recurrence using twice daily compared to once daily enoxaparin with no significant increase in bleeding (Merli et al, 2001). Insertion of an inferior vena cava (IVC) filter is not recommended for recurrence alone. An increased risk of VTE recurrence has been shown in cancer patients, despite IVC filter use (Elting et al, 2004). In non-cancer patients, routine use of IVC filters reduces pulmonary embolism (PE) but increases deep vein thrombosis (DVT) and has no impact on overall survival over an 8-year follow-up [The Pr
evention du Risque d’Embolie Pulmonaire par Interruption Cave (PREPIC) Study Group, 2005].

Long-term (>6 months) therapy The role of anticoagulation after 6 months of treatment has not been extensively studied. It is likely that LMWH is more effective than VKA in patients with active malignancy but the optimal dose in this situation is not clear. With progressive disease, quality of life and the patient’s wishes should be considered, because the risk of thrombosis increases with metastatic disease (Wun & White, 2009). It is reasonable to ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 170, 640–648

consider an alternative oral anticoagulant if the patient does not wish to continue with daily injections after 6 months and in these circumstances oral direct inhibitors of coagulation factors may offer advantages over warfarin for the reasons stated above. There is little evidence for loss of bone density in situations where LMWH has been used for prolonged periods of time (Rodger et al, 2007). If treatment is thought to have eradicated the malignant disease then anticoagulation can reasonably be discontinued after 6 months. Risk prediction measurements, such as Ddimer, have not been evaluated in this circumstance but stage IV cancer, brain lung, ovarian, gastrointestinal and multiple active cancers, along with myeloproliferative and myelodysplastic disorders, neurological disease with leg paresis and stage III cancers, were all found to predict the risk of recurrence of VTE in patients with a first cancer-associated thrombosis following discontinuation of a finite period of anticoagulation (Chee et al, 2014). Thrombocytopenia. The presence of thrombocytopenia demands reassessment of the risk-benefit balance of anticoagulation. However, in the first 3 months after thrombosis the risk of recurrence is particularly high and so every effort should be made to allow safe administration of anticoagulant therapy. Consensus suggests that full anticoagulation is without excessive risk whilst the platelet count remains above 50 9 109/l (Carrier et al, 2013). One approach is to attempt to support the platelet count to allow full dose anticoagulation to continue throughout the period of highest risk of recurrence of the VTE. Temporary insertion of an IVC filter is warranted if persistent thrombocytopenia or other bleeding risk precludes anticoagulation. Heparin-induced thrombocytopenia must be excluded in patients developing thrombocytopenia during heparin therapy. If the platelet count cannot be elevated then 50% dose LMWH can be given to patients with a platelet count of 25– 50 9 109/l. Below this level we advise withholding anticoagulation, although prophylactic doses have been used with reported benefit (Drakos et al, 1992).

Recommendations  In patients with cancer-associated thrombosis initial treatment should be with LMWH for 6 months, if tolerated (1A).  Warfarin and other oral anticoagulants are acceptable alternatives if LMWH is impractical and anticoagulation is indicated (1A).  An IVC filter should only be inserted when there is a strong contraindication to anticoagulation and should be removed if possible as soon as anticoagulation is possible (2C).  In the presence of active malignancy, anticoagulation should be continued, taking patient status and wishes and bleeding risk into consideration. There is a ratio643

Guideline nale but little direct evidence for preferring to continue to use LMWH (2B).  When the platelet count is <50 3 109/l platelet support should be given to elevate the count to >50 3 109/l to allow full dose anticoagulation, especially in the immediate period following thrombosis development (2D).  Patients with platelet counts between 25 and 50 3 109/l should have frequent assessment to allow decisions on LMWH to be made (2D).  If the platelet count remains <25 3 109/l, full anticoagulation should be avoided (1D).

Incidental venous thrombosis Asymptomatic venous thrombosis is a relatively common finding in high risk patients screened for DVT or PE (Meignan et al, 2000). In a meta-analysis of 12 studies reported between 1996 and 2007, including over 10 000 chest computerized tomography (CT) scans being undertaken for reasons other than suspicion of PE, the estimated prevalence of incidental PE was 2
6% (95% CI 1
9–3
4) (Dentali et al, 2010). Incidental PE rates were higher in cancer patients (odds ratio 1
80, 95% CI 1
18–2
75) who had a weighted mean prevalence of 3
1% (95% CI 2
2–4
1), and were more often detected when CT scanning with a slice thickness of <5 mm. Furthermore, if a CT pulmonary angiography protocol (with slice thickness of ≤1
5 mm) was systematically included when undertaking cancer-staging CT of thorax, 18/407 patients (4
4%) were found to have incidental PE, 7 of which were not detected on standard CT (Browne et al, 2010). The Haemostasis and Malignancy Scientific Sub-Committee of the International Society on Thrombosis and Haemostasis (Khorana et al, 2012) recommend the term ‘incidental’ rather than ‘asymptomatic’ because in 40–50% of these cases patients will have PE-related symptoms that have either been overlooked or attributed to their cancer (O’Connell et al, 2006; Sahut D’Izarn et al, 2012; Shteinberg et al, 2012). Most studies comparing incidental PE with symptomatic PE report similar underlying risk factors, such as advanced cancer stage (Cronin et al, 2007; Browne et al, 2010; Dentali et al, 2010; Di Nisio et al, 2010; Font et al, 2011; Sahut D’Izarn et al, 2012) and a similar distribution of pulmonary arteries affected, with around 50% involving main or lobar arteries and only 10–13% being sub-segmental PE (O’Connell et al, 2006; Sahut D’Izarn et al, 2012; Shteinberg et al, 2012; den Exter et al, 2013a). However symptomatic patients more often have bilateral PE (Font et al, 2011) and a have a higher overall thrombotic burden (den Exter et al, 2013b). The natural history of incidental PE in cancer patients has been poorly studied. Higher 6-month mortality in cancer patients with venous thrombosis has been demonstrated to be independent of whether the thrombosis is symptomatic or incidental (Dentali et al, 2011). A retrospective case control study comparing 70 patients with incidental PE with 137 644

cancer patients without venous thrombosis, but matched for age, cancer type and stage, demonstrated a higher 6-month mortality (HR 1
97, 95% CI 1
09–3
58) in the incidental PE patients (O’Connell et al, 2011). Studies comparing outcomes in cancer patients with incidental PE to those with symptomatic PE (when both receive anticoagulant therapy), suggest a similar risk of symptomatic recurrent thrombosis, major bleeding and mortality (den Exter et al, 2011; Sahut D’Izarn et al, 2012). Font et al (2011) noted a slightly higher recurrent thrombosis rate, but no difference in overall survival, in cancer patients with symptomatic DVT or PE compared to those with initial incidental DVT or PE, despite the latter receiving a shorter period of anticoagulation. Incidental DVT in cancer patients undergoing a staging CT scan of abdomen and pelvis involving IVC, iliac, common femoral or splanchnic veins may be as common as incidental PE (Cronin et al, 2007; Di Nisio et al, 2010; Douma et al, 2010). A review of 2591 consecutive abdominal CT scans (Ageno et al, 2012) identified incidental abdominal vein thrombosis most commonly in patients with cirrhosis. The prevalence of incidental abdominal vein thrombosis was 2
5% among 1442 cancer patients (95% CI 1
78–3
48). Patients with gastro-intestinal tract malignancy appear to have a particularly high rate for incidental abdominal or lower limb DVT (Singh et al, 2010). Retrospective short term follow-up of small cohorts of patients with incidental PE or DVT who did not receive anticoagulant therapy because the thrombosis was missed in the initial CT report or because the patient was deemed to be at high bleeding risk, show a symptomatic recurrent thrombosis risk of 5–11% within 3 months (Gladish et al, 2006; Browne et al, 2010; Douma et al, 2010). In a retrospective review of 113 lung cancer patients with incidental PE, 62 who did not receive anticoagulant treatment had a higher mortality rate (HR 4
1, 95% CI 2
3–7
6) despite both groups having similar cancer stage and performance status (Sun et al, 2010). Given the absence of randomized studies of anticoagulant therapy in cancer patients with incidental venous thrombosis, optimal management remains unknown. However the low quality evidence available suggests that, in cancer patients, incidental PE and DVT are indicative of a generalized prothrombotic state and can be associated with a significant risk of early recurrent thrombosis and similarly poor survival rate as symptomatic thrombosis. Current American College of Chest Physicians guidance favours anticoagulant therapy for incidental venous thrombosis where the diagnosis is secure (Kearon et al, 2012). The one exception may be patients with isolated sub-segmental PE, which may have a more benign natural history (Eyer et al, 2005), but there is no clear consensus on this at present (den Exter et al, 2013c). The merits of anticoagulation for symptomatic abdominal vein thrombosis require individual risk assessment (Tait et al, 2012), and it is recommended that cancer patients with incidental abdominal vein thrombosis are considered similarly. ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 170, 640–648

Guideline

Recommendations  Cancer patients with incidental pulmonary embolus or DVT should be therapeutically anticoagulated as for symptomatic disease (1C).

Screening for cancer in patients with apparently unprovoked VTE The association of cancer and VTE is well recognized. A systematic review of 14 studies and an additional abstract (Carrier et al, 2008) reported the prevalence of undiagnosed cancer in patients with unprovoked VTE as 6
1% (95% CI 5
0–7
1) at presentation, increasing to 10
0% (CI 8
6–11
3) at 12 months. This review suggests that an extensive screening strategy using CT of the abdomen and pelvis increases the detection rate of previously undiagnosed cancer from 49
4% (CI 40
2–58
5) to 69
7% (CI 61
1–77
8). The further question is whether earlier cancer detection affects outcomes for patients in these clinical circumstances. In the SOMIT (Screening for Occult Malignancy in Patients with Symptomatic Idiopathic VTE) study, 99 patients were randomized to extensive screening for occult cancer and 102 to no further testing (Piccioli et al, 2004). Extensive screening identified occult cancer in 13 (13
1%) patients, with a single (1
0%) further malignancy becoming apparent during the 2-year follow-up. In the control group a total of 10 (9
8%) malignancies became apparent during the 2-year follow-up. Mean delay to diagnosis was reduced from 11
6 to 1
0 month (P < 0
001). Cancer-related mortality during the 2-year follow-up period occurred in two (2
0%) of the 99 patients in the extensive screening group versus four (3
9%) of the 102 control patients [non-significant absolute difference 1
9% (95% CI 5
5–10
9)]. A year after publication, the data from the SOMIT trial were used to perform a decision analysis (Di Nisio et al, 2005). The screening tests were divided into several possible strategies and the number of detected cancers and the number of patients investigated further for what eventually turned out to be a benign condition were calculated for each strategy. As an example, CT of the abdomen combined with sputum cytology and mammography detected 12 of the 14 patients with cancer and had one false-positive result. The authors concluded that screening for cancer with a strategy including abdominal/pelvic CT with or without mammography and/or sputum cytology appears potentially useful although its costeffectiveness needs confirmation in a large trial. NICE further examined these data and, without considering further data from the larger non-randomized study discussed below, concluded that a strategy based on abdominal/ pelvic CT plus mammography seemed to provide the best value-for-money leading to a (weak) recommendation to ‘consider further investigations for cancer with an abdomino-pelvic CT scan (and a mammogram for women) in all patients aged over 40 years with a first unprovoked DVT or ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 170, 640–648

PE who do not have signs or symptoms of cancer based on initial investigation’ (NICE, 2012). A larger, prospective cohort study compared limited and extensive cancer screening strategies (Van Doormaal et al, 2011b); all patients underwent baseline screening consisting of history, physical examination, basic laboratory tests and chest X-ray. Of the 630 patients studied, 342 were seen in hospitals that performed additional extensive screening with CT chest/abdomen and mammography and 288 in hospitals that did not. The initial limited screening detected malignancy in 12/342 (3
5%) and 7/288 (2
4%) respectively. In hospitals performing extensive screening, 302 of the 330 remaining patients underwent screening and suspicion of cancer was raised in 91 (30% of 302) and confirmed in six (2
0% of the 302), of which three were potentially curable. During a median 2
5 years of follow-up, cancer was diagnosed in an additional 12 patients in the extensive screening group and an additional 14 patients in the limited screening group. In the extensive screening group 26 patients (7
6%) died compared with 24 (8
3%) in the limited screening group; adjusted HR 1
22 (95% CI 0
69–2
22). Of these deaths, 17 (5
0%) in the extensive screening group and 8 (2
8%) in the limited screening group were cancer-related; adjusted HR 1
79 (95% CI 0
74–4
35). Although this study was abandoned as futile, the authors concluded that the low yield of extensive screening and lack of survival benefit do not support routine screening for cancer with abdominal and chest CT scan and mammography in patients with a first episode of unprovoked VTE. Clinicians are left in a difficult situation as it appears that screening does identify malignancies at an earlier stage (Monreal et al, 2004; Piccioli et al, 2004) but cancer diagnosed at the same time as, or within 1 year after, an episode of VTE is associated with an advanced stage of cancer and a poor prognosis (Sorensen et al, 2000). Extensive screening, and even counselling patients about screening, can cause considerable anxiety. Further radiology-based screening results in radiation exposure [a CT abdomen is the equivalent of 400 chest X-rays and 3
3 years of background radiation (Davies et al, 2011)] and unnecessary further testing in those with false positive results. Cancer is more prevalent in those with bilateral DVTs (Rance et al, 1997), early VTE recurrence (Prandoni et al, 1992), or very high D-dimers [>4000 lg/l fibrinogen equivalents units (FEU) (Beckers et al, 2006; Schutgens et al, 2005), >8000 lg/l FEU (Paneesha et al, 2006)], and if universal screening is not implemented these may be may useful in selecting those for further investigation.

Recommendations  In patients over 40 years old with unprovoked VTE, screening for cancer with CT scan (and mammography for women) should be considered but not routinely performed (2C). 645

Guideline  There should be a lower threshold for screening those with bilateral DVT, very high D-dimers or an early recurrence of VTE (2C).

Review process Members of this writing group will inform the writing group chairman if any new pertinent evidence becomes available that would alter the strength of the recommendations made in this document or render it obsolete. The document will be archived and removed from the BCSH current guidelines website if it becomes obsolete. If new recommendations are made, an addendum will be published on the BCSH guidelines website (http://www.bcshguidelines.com/). If minor changes are required due to changes in level of evidence or significant additional evidence supporting current recommendations a new version of the current guidance will be issued on the BCSH website.

All of the authors were involved in the production of the final document. HGW chaired the guideline group; the other authors are all BCSH Haemostasis and Thrombosis Taskforce representatives. The members of the BCSH Haemostasis and Thrombosis Taskforce at the time of the development of the guidance were those above along with: Elaine Gray, clinical scientist, NIBSC; Ian Jennings, clinical scientist, UK NEQAS coagulation; Isobel Walker, medical director, UK NEQAS coagulation; and Andrew Mumford, Senior Lecturer in Haematology, University of Bristol. The authors would like to thank them and the BSH sounding board for their help in producing this guidance.

Disclaimer While the advice and information in this guidance is believed to be true and accurate at the time of going to press, neither the authors, the British Committee for Standards in Haematology or the publishers accept any legal responsibility for the content of this guidance.

Acknowledgements HGW, DK, ML, RCT and MM performed the review and took responsibility for writing individual sections of the text.

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