Cancer dacus 21 ottobre 2012 jco

The optimal duration of low molecular weight heparin for the treatment of cancer-
related deep vein thrombosis: the Cancer-DACUS Study
Running Title: Residual vein thrombosis and low molecular weight heparins 1Sergio Siragusa, 1Giorgia Saccullo, 1Alessandra Malato, 2Walter Ageno, 3Davide Imberti 4Doris Mascheroni, 5Eugenio Bucherini, 6Pina Gallucci, 7Andrea D’Alessio, 8Tullia Prantera 9Pietro Spadaro, 10Stefano Rotondo, 11Pierpaolo Di Micco, 12Vincenzo Oriana, 13Oreste Urbano, 14Francesco Recchia, 15Angelo Ghirarduzzi, 1Lucio Lo Coco, 1Salvatrice Mancuso, 1Mariasanta Napolitano, 16Antonio Russo, 17Alessandra Casuccio, 18Giovam Battista Rini Affiliations:
1Cattedra ed Unità di Ematologia con trapianto, Dipartimento di Medicina Interna e Specialistiche DIMIS, Università degli Studi di Palermo, Palermo 2Dipartimento di Medicina Clinica e Sperimentale, Università dell’Insubria, Varese 3Dipartimento di Medicina Interna, Ospedale di Piacenza 5Modulo Angiologia, Ospedale di Faenza, Italy 6CROB Basilicata, Rionero in Volture, Italy 8Ospedale S. Giovanni di Dio, Crotone, Italy 10Centro Studi Neurolesi, Messina, Italy 12Azienda ospedaliera di Reggio Calabria, Reggio Calabria, Italy 15Azienda Ospedaliera di Reggio Emilia Arcispedale S. Maria Nuova, Reggio Emilia 16Dipartimento di Scienze Chirurgiche ed Oncologiche, Sezione di Oncologia, Università 17Dipartimento di Biomedicina Sperimentale e Neuroscienze Cliniche (BIONEC), Università 18Cattedra di Medicina Interna, Dipartimento di Medicina Interna e Specialistiche DIMIS, Università degli Studi di Palermo, Palermo Cattedra ed U.O. di Ematologia con trapianto Dipartimento di Medicina Interna e Specialistica (DIMIS) Via del Vespro 127, 90127 Palermo, Italy Abstract
Purpose: We evaluated the role of Residual Vein Thrombosis (RVT) to assess the optimal duration of anticoagulants in cancer patients with Deep Vein Thrombosis (DVT) of the lower limbs. Patients and Methods: Patients with active cancer and a first episode of DVT who were treated with Low Molecular Weight Heparin (LMWH) for 6 months were eligible for the study. Patients were managed according to RVT findings: those with RVT were randomized to continue with LMWH for 6 additional months (Group A1) or to discontinue it (Group A2), while patients without RVT stopped anticoagulant treatment (Group B). Primary endpoint was recurrent VTE and secondary endpoint was major bleeding. The patients were followed up for one year after LMWH discontinuation. Results: Between October 2005 and April 2010, 409 patients were evaluated and 347 were enrolled in the study. RVT was detected in 242 (69.7%) patients; recurrence occurred in 15.1% of patients randomized to continue (Group A1) and in 21.9% of those who discontinued LMWH (Group A2). Only 2.8% of patients without RVT experienced a recurrent event (Group B) (p<0.0005). Three major bleeding events occurred in Group A1 and two events each in Groups A2 and B (p=0.880). Overall, 42 (12.1%) patients died, during 12-months follow-up, due to cancer progression; no statistical significant difference among the groups (p=0.366) were found. Conclusion: In cancer patients with a first episode of DVT, absence of RVT identifies a population at a low risk for recurrent thrombotic events. (ClinicalTrials.gov: number NCT00450645) Introduction
Venous thromboembolism (VTE) is a frequent complication in cancer patients that can affect overall survival and quality of life (1-3). Management of deep vein thrombosis (DVT) and/or pulmonary embolism (PE) may be difficult in this population because of the high risk of both recurrent events and major hemorrhages, even if adequate vitamin K antagonist (VKA) therapy is administered (4). It has been reported that the use of low molecular weight heparin (LMWH) is more effective than VKA without increasing the risk for major bleeding in the first 6 months of therapy (5), and this treatment is now recommended as the first option for all cancer patients with acute VTE (6-7). There is less evidence regarding the duration of anticoagulant treatment; current guidelines suggest that patients with cancer-related DVT should be treated for 6 months or even longer (6) if the cancer is still active, but such recommendations do not rely on data from randomized trials, hence the uncertainty. In the non-cancer patients, the risk of recurrence is usually greatest in the first year after withdrawal from anticoagulant treatment and gradually diminishes (8), while the increased bleeding risk may offset the benefits of prolonged VKA (9). For this reason, new markers, such as residual vein thrombosis (RVT) and D-dimers, have been proposed to individualize the duration of VKA treatment for the secondary prevention of VTE (10-13). Results from prospective studies have shown that the absence of RVT or negative D-dimers may drive safe withdrawal of VKA treatment after 3-6 months from the index DVT (10). On the other hand, the presence of RVT has been associated with an increased risk for recurrent venous thrombosis in idiopathic and provoked DVT (11-13). In comparison to D-dimers, RVT has potential advantages in patients with chronic activation of coagulation or inflammation, since it is not influenced by factors acting on blood coagulation; this makes such parameter particularly suitable for cancer patients. However, it is still unknown whether RVT may be used to optimize the duration of LMWH treatment in cancer patients, a population at a high-risk for recurrent events. We therefore performed a randomized study in patients with a first episode of cancer- related symptomatic DVT of the lower limbs to test the hypothesis that RVT may be used to establish the optimal duration of LMWH treatment. Study population
Inclusion criteria were age older than 18 years; symptomatic proximal DVT detected by compression ultrasonography (C-US), active cancer defined as metastatic or locally- advanced lung, gastrointestinal (stomach, colon, or rectum), pancreatic, breast, ovarian, or head and neck cancer, blood cancer and treatment with LMWH for 6 months after the index event (5). Patients with active cancer and a DVT episode occurring after cancer surgery were also eligible for the study. Eligible patients were enrolled after written informed consent was Patients were excluded if they had: Eastern Cooperative Oncology Group score > 2; previous VTE; antiphospholipid antibody syndrome, or other known thrombophilic states (such as deficiency in antithrombin, protein C and S, homozygosity for FV Leiden or factor II G20210A mutations or heterozygous combinations thereof); other conditions requiring prolonged anticoagulation; active bleeding or bleeding requiring hospitalization, transfusion or surgical intervention in the past 4 weeks; intracranial bleeding over the past 6 months; high risk of bleeding (international normalized ratio or activated partial thromboplastin time ratio above 1.3, or a platelet count lower than 75×109/L); known active gastric or duodenal ulcer; known cerebral metastases; severe and uncontrolled hypertension; creatinine clearance < 30 ml/min; severe liver insufficiency; unavailability for follow-up. The study was carried out in accordance with the provisions of the Declaration of Helsinki and local regulations. The protocol was approved by the institutional review board at each study center, and written informed consent was obtained from all patients before Study design and procedures
This multicenter prospective study was carried out between October 2005 and April 2010. At the time of enrolment in the study, at 6 months from the index event, all patients underwent C-US of the affected leg and images were obtained from the transverse section only. Lumen compressibility was then evaluated by gentle pressure of the probe; RVT diameter was taken by measuring the distance between the anterior and posterior walls of the vein, on freeze-frame B-mode images, during compression with the ultrasound probe (14). The examination was performed with the patient in the supine position with the leg externally rotated and slightly flexed at the knee. Measurements were taken at the common femoral vein, 1 cm below the inguinal ligament, and at the popliteal vein, at the most prominent crease in the mid-popliteal fossa. The RVT calculation was made as previously described (12): RVT = vein diameter during compression (diameter b) x 100/vein diameter before compression (diameter a). RVT was arbitrarily scored as “absent” when the value was < 40% of the vein diameter. The patient was considered to have RVT when a persisting thrombus was shown to be present in at least one of the two examined vein segments (Figure 1). Patients with RVT were then randomized to either stop or continue LMWH (Nadroparine), administered at 75% of full dose (97 UI antiFXa/kg/twice daily) for 6 additional months (Group A2 and A1, respectively). This dosage was chosen accordingly to the results of randomized studies that evaluated LMWH in comparison to VKA in cancer patients with VTE (5, 15). All patients with no evidence of RVT stopped anticoagulation (Group B) (Figure 2). After the first C-US test performed at the time of enrolment in the study, patients underwent additional testing only when recurrence was clinically suspected. Randomization and masking
For each different institution, after signing the informed consent form, patients with RVT were randomized to either stop or continue LMWH, using sequentially numbered, sealed, opaque envelopes prepared from a list of computer-generated pseudo-random numbers. The sequences were balanced in blocks of 10. Patients and treating physicians were Study outcomes and follow-up
Patients were followed up for one year after LMWH discontinuation (Figure 2) and were seen at the clinical center at intervals of 3 months. Primary endpoint was recurrent VTE and secondary endpoint was major bleeding. Patients were instructed to contact the clinical center if symptoms suggestive of VTE or bleeding developed. In cases of recurrence, results of C-US were compared with those of the previous examination. Diagnosis of recurrent DVT was made if a previously fully compressible segment (contralateral or ipsilateral) became no longer compressible, or if an increase of > 4 mm in the diameter of the residual thrombus during compression was detected (16); in undetermined cases, repetition of the test (after 5-7 days) or contrast venography was performed. In patients with suspected pulmonary embolism, the diagnosis of recurrence was based on objective algorithms with the use of clinical probability, ventilation– perfusion lung scanning or helical CT (17-18). Major bleeding was defined as a decrease in hemoglobin > 2.0 g/dl, intracranial or retroperitoneal bleeding, bleeding requiring surgical intervention or blood transfusion, or any other bleeding considered clinically relevant by the physician in charge requiring suspension of anticoagulation and the use of hemostatic approaches (9). Minor bleeds comprised all other bleeding events. All suspected outcome events and deaths were evaluated by a central adjudication committee whose members were unaware of the patient's name, the center where the patient had been enrolled, the results of RVT assays, and the group assignment. Committee members also reviewed the results of all clinical investigations without knowing the patient's name, the group assignment, or the center where RVT had been performed. Statistical analysis
The sample size was calculated taking into account an incidence of 20% for recurrent thrombotic events and 5% of complications for the group with the best prognosis (4). An overall sample size of 300 patients (100 for each study group) was calculated to achieve a power of 80% to document a difference of at least 15% in at least one of the different head- to-head comparisons, based on the Bonferroni method for distributing type I error (0.05) among multiple comparisons. In order to monitor the safety of the trial, an interim analysis was planned after enrolment of two-thirds of the total patient population. Prior to study onset, we set up an internal quality control system to assess inter- and intra-examiner reproducibility for RVT analysis among operators by the use of the unweighted Cohen’s kappa (k) test (19). Baseline differences between groups were assessed by the chi-square test (Yates’ correction) for categorical variables, and the univariate analysis of variance (ANOVA) for parametric analyses. Data were analyzed on an intention-to-treat basis. Kaplan-Meier curve was plotted to estimate the cumulative probability of absence of symptomatic recurrent thrombosis. Hazard Ratios (HRs) and their 95% confidence intervals (CIs), calculated using the Cox proportional hazards model were adjusted for age, sex, previous surgery and presence of metastasis. Data were analyzed using Epi Info software (version 6.0, Centers for Disease Control and Prevention, Atlanta, GA, USA) and SPSS Software (version 14.0, SPSS Inc., Chicago, Il, USA). All p-values were two-sided; p-values < 0.05 were considered Patients and treatment groups
Of the 409 evaluated patients, 62 were excluded: 9 because they did not provide informed consent, 18 because they required long-term anticoagulation, 7 because of low platelet count, 12 for recent surgery, 3 for cerebral metastases, and the remaining 13 for organ failure. A total of 347 patients were therefore included in the study. No patient was lost to follow-up. RVT was detected in 242 (69.7%) patients who were then randomized to continue (119 patients; group A1) or to discontinue (123 patients; group A2) anticoagulant treatment with LMWH. RVT was absent in 105 (30.3%) patients (group B). Baseline patient characteristics are reported in Table 1. Cancer characteristics, site and chemotherapy treatments in the different groups are reported in Tables 1 and 2. There were no statistically significant differences among groups in the prevalence of metastatic cancer, different cancer types and ongoing chemotherapy. Twenty-three percent of patients had a hematologic cancer, Outcomes
During the overall follow-up, recurrent events occurred in 18/119 (15.1%) of RVT patients randomized to continue and 27/123 (21.9%) of those who discontinued LMWH. In patients without RVT (105, 30.3%), recurrent events occurred in 3 (2.8%) cases (A1 vs A2, p= 0.150; B vs A1, p=0.002; B vs A2, p<0.0005; Log Rank test) (Table 3 and Figure 4). The recurrence rate x100 person-year was 11.3 in Group A1, 26.7 in Group A2 and 3.0 in Group B. Most of these events were deep venous thromboses of the lower limbs; in 12 of 48 (25%) cases, thromboses occurred in the contralateral leg. The adjusted hazard ratio (HR) for recurrent DVT between RVT groups (Group A2 vs A1) was 1.37 (95% confidence interval [CI], 0.7–2.5; p=0.311). The adjusted HR between group A1 versus RVT-negative group (B) was 5.68 (CI 1.6–19.4; p=0.006). The adjusted HR between group A2 versus the RVT-negative group (B) was 7.96 (CI 2.4–26.3; p=0.001). Among participants with RVT, continuation of heparin therapy reduced the risk of recurrent VTE by about 30% (6.8 Bleeding events was reported in Table 3. During 12-months follow-up, 3 major bleedings occurred in group A1, and 2 events occurred in both groups A2 and B, respectively (p=0.880). Among patients randomized to continue LMWH for additional 6 months, patients’ compliance was high: 15 of the 119 patients interrupted LMWH for less of 5 days during Overall, 42 (12.1%) patients died during 12-months follow-up, all because of cancer progression: 12 patients (10.1%) died in group A1, 19 (15.4%) in group A2 and 11 (10.5%) Discussion
Our results suggest that RVT assessment is useful for establishing the optimal duration of cancer-related DVT, as we previously observed in the non-cancer population (12- 13). In fact, RVT assessment has identified a subset of patients at a lower risk of recurrence (about 30%) that can safely stop anticoagulation. In high-risk patients (those with persistent RVT), our data show that interruption of LMWH treatment is associated with a high risk of recurrence even if anticoagulation is continued for up to 1 year. LMWH is currently considered the standard of care for cancer-related DVT due to its favorable safety and efficacy profile even if its optimal duration is still debated. International guidelines recommend to continue the treatment while the neoplasm is active (6) but cancer populations differ substantially in terms of type, stage, histology and, consequently, treatment choice (20). On this basis, the optimal management of anticoagulant therapy should be based on the possibility of tailoring treatment, according to the type and characteristics of underlying cancer as well as concomitant chemotherapy. Such individual-based approach has been experimented in non-cancer population, where individual markers for establishing the optimal duration of anticoagulant treatment have been proposed (10-13). Residual Vein Thrombosis and D-dimers have been extensively evaluated and the results of clinical studies suggest that, after an initial course of treatment with VKA, a negative D-dimer or the absence of RVT identify patients who can stop treatment, independently from the pathogenesis of the index DVT. These data are lacking in the cancer population; among these individual markers, RVT looks more suitable than D- dimer since it is insensitive to factors affecting blood coagulation (such as infections or cancer) and it can be performed without interrupting anticoagulation (11-13). The results of our study have obvious advantages in clinical practice: in low-risk patients, short-term anticoagulation reduces the clinical burden for both the patient and the healthcare system, and substantially reduces the overall risk of bleeding that is inherent with prolonged anticoagulant treatment. These advantages are supported by the fact that we used a simple and reproducible method for tailoring LMWH duration in cancer-related DVT. This strategy is important in practical terms as it can be easily and broadly applied. Another consideration regards mortality among the groups; overall almost 12% of patients died during the follow-up. This rate was similar regardless of RVT findings or LMWH duration. However, our study design does not allow us to look at potential advantages in terms of reducing mortality among groups, as previously reported in patients on LMWH (22-23). As in the non-cancer population, more than 20% of the recurrent thromboses occurred in the contralateral leg; whether this fact indicates RVT as a marker of an underlying pro- thrombotic state, thus triggering a sustained hypercoagulability (24), need to be confirmed in This study has limitations; first, the trial was not blinded. However, committee members who were unaware of the results of RVT detection and treatment assignments assessed recurrent events, thus reducing the risk for diagnostic suspicion bias. Moreover, the rates of events in the treated and untreated patients are in the range of those reported in the literature (4, 25). Second, some concerns may arise about the reproducibility of RVT detection. Prior to the DACUS studies, we tested RVT assessment on a consecutive series of 64 non-compressible venous segments (in popliteal and common femoral veins). The result of inter- and intra-observer variation assessment among operators was shown to be adequate (κ =0.95; 95% CI, 0.88 to 1.00) (11, 26). Third, RVT assessment was performed only at the study entry. We can not exclude that during follow-up some patients, with originally absence of RVT, could have had abnormal results on repeated testing, providing a detectable warning sign of recurrent hypercoagulability and an increased risk of thrombosis. Repeated RVT in patients with an originally absence of residual thrombus may be useful in detecting a late relapse even if asymptomatic, but this hypothesis should be assessed in future studies. Fourth, although the study was large enough to detect significant differences between groups in the frequency of the recurrent venous thromboembolism, it was not large enough to make a definitive assessment of the relative risk of bleeding. Fifth, in patients without RVT, the incidence of recurrent VTE was lower (3%) than previously reported in cancer population. However, if we take in account all patients evaluated in the study (both with and without RVT), the rate of recurrent VTE was high as 14% an average rate similar to that reported (4- 7). Finally, the robustness of the association between RVT and recurrent VTE has been recently evaluated in two meta-analyses (26, 27); the results have shown a weaker association than that previously reported in prospective trials. However, the study by Tan et al. (26) found across-study heterogeneity (I2=74%) when the analysis was confined to patients with unprovoked DVT, thereby limiting the study conclusions to such patients. The study by Carrier et al. (27) was unable to adjust for potential covariates. An updated systematic review and patient-level meta-analysis on this topic is currently ongoing. In conclusion, our results indicate that the absence of RVT identifies cancer patients at a low risk for recurrent thrombotic events. This ability is important in driving a management strategy for both the prevention of recurrences and the selection of a DVT patient population who may benefit from a short period of anticoagulation. Authors’ contributions
Sergio Siragusa: study design, data analysis and interpretation, writing the manuscript Giorgia Saccullo and Alessandra Malato: study design, data collection, analysis and Walter Ageno and Davide Imberti: data collection and writing the manuscript Alessandra Casuccio: data analysis and interpretation, writing the manuscript References
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^P-value refers to chi-square test unless specified; § Univariate analysis of variance (ANOVA) test; *In the past 3 months; **In the past 3 months or ongoing; Footnote:
Group A1: patients with RVT who continued LMWH for additional 6 months Group A2: patients with RVT randomized to stop LMWH Group B: patients without RVT who stopped LMWH Table 2. Cancer site and chemotherapy by treatment group

Footnote:
Group A1: patients with RVT who continued LMWH for additional 6 months Group A2: patients with RVT randomized to stop LMWH Group B: patients without RVT who stopped LMWH Table 3. Recurrent thromboembolic and bleeding events by treatment group and cancer
18/119(15.1) 27/123 (21.9) 3/105 (2.8) <0.0005 DVT and PE (pulmonary embolism), N° (%) DVT in not previous affected leg, N° (%) * P-value refers to chi-square test unless specified. ** Chi-square test for the comparison of two proportions, expressed as percentage. Footnote:
Group A1: patients with RVT who continued LMWH for additional 6 months Group A2: patients with RVT randomized to stop LMWH Group B: patients without RVT who stopped LMWH Figure legends
Figure 1. Evaluation of residual vein thrombosis.
RVT calculation = vein diameter during compression (diameter b) x 100 / vein diameter Figure 2. Study design
A1 indicates patients with RVT who continued LMWH for additional 6 months; A2 indicates patients with RVT randomized to stop LMWH treatment; B indicates patients without RVT Figure 3. Trial profile
Figure 4. Kaplan-Meier curve for recurrent VTE in the three groups at 12 month
follow-up.
Group B= patients without RVT and without anticoagulation; Group A1 and Group A2 patients with RVT which continue (for 6 months) or stop LMWH treatment. Enrollment
Excluded (n= 62) ♦ Not meeting inclusion criteria (n=53) ♦ Declined to participate (n=9) Allocation
♦ Received allocated intervention (n=119) ♦ Received allocated intervention (n=123) Analysis
Figure 4. Kaplan-Meier curve for recurrent VTE in the three groups at 12-month
follow-up

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