Clinical Course of Venous Thromboembolism in Patients with Pancreatic Cancer: Insights from the RIETE Registry

FRERE, CORINNE; TRUJILLO-SANTOS, JAVIER; FONT, CARME; SAMPÉRIZ, ÁNGEL; QUINTAVALLA, ROBERTO; GONZÁLEZ-MARTÍNEZ, JOSÉ; VÁZQUEZ, FERNANDO JAVIER; LIMA, JORGE; FARGE, DOMINIQUE; MONREAL, MANUEL

THROMBOSIS AND HAEMOSTASIS

SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN

Año: 2018 vol. 118 p. 1119 - 1122

0340-6245

While numerous studies reported that the risk of venousthromboembolism (VTE) in cancer patients varies widelyaccording to primary cancer site,1 there is a paucity of datacomparing the long-termclinical course of VTE during anticoagulanttherapy per site of cancer. Mahé et al recentlyhighlighted that VTE-related outcomes may differ acrosspatients with breast, prostate, colorectal or lung cancer.2Pancreatic cancer (PC) is associatedwith the highest ratesof VTE,1?6 with an incidence ranging from5 to 41% in specificPC cohorts,7?18 and up to 67% in post-mortem series.19However, no specific data exist in the literature regardingthe risk of recurrent VTE or major bleeding during anticoagulanttherapy in PC patients.Using data from the Registro Informatizado EnfermedadTromboEmbólica (RIETE Registry),2we aimed to compare theVTE clinical presentation and outcome during the course ofanticoagulant therapy between PC patients and other cancerpatients. Rationale, design and methodology of RIETE havebeen extensively described elsewhere.20Between March 2001 and April 2016, among 10,961patients with active cancer and acute symptomatic VTEprospectively enrolled in the RIETE Registry, 497 had PC(localized 103, metastatic 394). In the overall studied population,most cancer patients were receiving specific cancertreatment, with either chemotherapy (n ¼ 5,575 [50.9%]),radiotherapy (n ¼ 1,376 [12.8%]) and hormonotherapy(n ¼ 1,099 [10%]) alone or in combination. At time of initialVTE diagnosis, metastatic disease was more frequent in PCthan in the other cancer patients (n ¼ 397 [79.2%] vs. 5,257[50.3%]; p < 0.0001). More than half of the total number ofinitial VTE eventswere pulmonaryembolism (PE) (n ¼ 5,699[52%]), and the proportions of cancer patients presentinginitially with PE did not differ between PC and other cancerpatient groups. Compared with other groups, metastatic PCpatients who presented a deep vein thrombosis (DVT) initiallyweremore likely to have a proximal DVT. This difference versus other groups was statistically significant: n ¼ 141(74%) of all VTE were proximal DVT among metastatic PCpatients compared with n ¼ 31 (60%) in localized PC,p < 0.05; compared with n ¼ 1,708 (68%) in other localizedcancer patients, p < 0.0001; and compared with n ¼ 1,754(71%) in other metastatic cancer patients, p < 0.0001. Longtermtherapy with low-molecular weight heparin (LMWH)was more frequently used in patients with localized PC(n ¼ 73 [74%]) than in those with other localized cancers(n ¼ 2,579 [51%]; p < 0.0001). Among patients with metastases,there were no differences between patients with PC(n ¼ 262 [75%]) or other cancers (n ¼ 3,436 [72%]). Fourteenper cent (n ¼ 14), 14% (n ¼ 47), 17% (n ¼ 808) and 35%(n ¼ 1764) of them, respectively, switched to vitamin Kantagonist (VKA) drugs. Median duration of all types ofanticoagulant therapy for VTE was significantly shorter inmetastatic PC patients than in other groups (p < 0.001),most likely because of their shorter survival.During the course of anticoagulant therapy, 586 (5.3%)recurrent VTE events (n ¼ 308 [52%] DVT and n ¼ 278 [48%]PE) occurred in this overall population. The incidence rate (IR)for total recurrent VTE events was non-significantly higher inpatients with localized PC than in those with other localizedcancers (15.51 events per 100 patient-years [95% confidenceinterval [CI], 6.22?31.97] vs. 9.58[95%CI,8.42?10.85]; p ¼ ns).Metastatic PC patients had a 2.1-fold higher risk for recurrentVTE than other metastatic cancer patients (31.65 events per100 patient-years [95% CI, 21.03?45.74] vs. 14.70 [95% CI,13.09?16.45]; p < 0.001) (►Table 1).Onmultivariate analysis,in PC patients, hospitalization (hazard ratio [HR], 0.76 [95% CI,0.62?0.93]; p ¼ 0.007), recent surgery (HR, 0.70 [95% CI, 0.54?0.91]; p ¼ 0.007), abnormal platelet count at baseline (HR,1.41 [95% CI, 1.12?1.77]; p ¼ 0.003) and metastasis (HR, 2.54[95% CI, 1.71?3.76]; p < 0.001) independently predicted therisk for recurrent VTE.Majorbleedingoccurredin406 patients (4.2%) intheoverallcancer population. The IRs for major bleeding were 8.87 (95%CI, 2.39?22.70) in localized PC patients, 15.82 (95% CI, 8.65?26.55) in metastatic PC patients, 6.83 (95% CI, 5.86?7.91) inlocalizedothercancer patients and12.86(95%CI,11.36?14.50)in metastatic other patients (►Table 1) and did not significantlydiffer between groups (p ¼ ns). However, when onlyconsidering PC patients, the rate of VTE recurrences duringanticoagulation was nearly twofold higher than the rate ofmajor bleeding (26.2 events per 100 patient-years [95% CI,18.25?36.44] vs. 13.47 events per 100 patient-years [95% CI,7.98?21.30]). Two hundred and seventy-two PC patients (54%)and 2,816 other cancer patients (25.7%) died during follow-up.Consistent with a recent analysis of the RIETE databaseincluding patients with breast, prostate, colorectal and lungcancer, our results confirm that the clinical course of VTEdiffers according to the primary cancer site. A retrospectivecohort of 542 cancer patients (with an unspecified number ofpancreas cancer patients) showed that in addition to femalegender, previous history of VTE, and TNM stage I/II, lung orbreast cancer were clinical predictors of recurrent VTE.21Another population-based study showed that brain, lung,ovarian cancer, myeloproliferative or myelodysplastic disordersand PC were associated with an increased hazard ofrecurrent VTE.22 In our study, the IR for recurrent VTE in PCpatients was 26 (95% CI, 18?36) per 100 patient-years whichis higher than in the other studied cancer patients with VTE,and higher than in previous studies in unselected cancerpatients,5 but comparable to the 27 (95% CI, 22?23) per 100patient-years IR in the RIETE sub-group of lung cancerpatients recently analysed.2Long-term treatment with LMWH is the current internationalstandard of care for the treatment of established VTE incancer patients.23 A major finding of our study is that PCpatients had a higher risk of recurrent VTE and a similar riskTable 1 Recurrent VTE and other outcomes during the course of anticoagulant therapyNon-metastaticpancreatic cancern ¼ 103Metastaticpancreatic cancern ¼ 394Non-metastaticother cancersn ¼ 5,207Metastatic other cancersn ¼ 5,257Years oftreatment45.12 88.47 2,578.16 2,068.32Months oftreatment541.43 1,061.67 30,937.90 24,819.87Events, per 100patient-yearsRecurrent DVT 4 8.87 (2.39?22.70) 19 21.5 (12.92?33.54)a 136 5.28 (4.43?6.24) 149 7.20 (6.09?8.46)cRecurrent PE 3 6.65 (1.34?19.43) 9 10.17 (4.64?19.31) 111 4.31 (3.54?5.19) 155 7.49 (6.36?8.77)Recurrent VTE 7 15.51 (6.22?31.97) 28 31.65 (21.03?45.74) 247 9.58 (8.42?10.85) 304 14.70 (13.09?16.45)cMajor bleeding 4 8.87 (2.39?22.70) 14 15.82 (8.65?26.55) 176 6.83 (5.86?7.91) 266 12.86 (11.36?14.50)Overall death 34 75.35(52.18?105?30)238 269(236?306)b688 26.69(24.73?28.76)b,c2,128 103 (98.0?107)cAbbreviations: DVT, deep vein thrombosis; PE, pulmonary embolism; VTE, venous thromboembolism.Note: Comparisons were made using patients with pancreas cancer without metastases as reference.ap < 0.01.bp < 0.001. Comparisons between both pancreas cancer with metastases and other cancers with metastases, and the same cancers withoutmetastases.cp < 0.001.Thrombosis and HaemostasisLetter to the EditorDownloaded by: INSERM Disc.Ist. Copyrighted material.ofmajor bleeding than other cancer patients, thus suggestingthe need for intensifying anticoagulation therapy in thissetting. While only a trend was observed towards morerecurrent VTE events in localized PC patients than in otherlocalized cancer patients, the difference was highly significantfor metastatic PC patients. These findings may contributeto better explain why VTE is associated with a shorteroverall survival in PC patients,13,17,24,25 independently ofperformance status, age or tumor burden.17 Such high risk ofrecurrent VTE in PC patients may be related by some primarytumor characteristics including enhanced tissue factor (TF)expression26 that was demonstrated to play a mechanisticrole in the pathogenesis of VTE.27 Concordantly, a preplannedregression analysis of the CATCH trial28 recentlyfound that patients in the highest quartile of TF antigen(>64.6 pg/mL) had an increased risk of VTE (relative risk, 3.3;95% CI, 2.1?5.1; p, 0.001). We also observed a higher rate ofrecurrent VTE in metastatic PC patients than in their nonmetastaticcounterparts, consistent with studies showingthat metastatic disease is a major risk factor for recurrentVTE.5,22,29,30In recent years, attempts have been made to improve VTErisk stratification in cancer patients. The accuracy and discriminatingpower of the Ottawa score to predict the risk forrecurrent VTE in cancer patients21 appeared modest in aretrospective study using data from the RIETE registry.31 Alltogether, these data highlight the need for new predictiontools necessarily including the various cancer types and theirdissemination status.In summary, our results confirmthat the clinical course ofVTE differs according to the primary cancer site. New scoresto predict the risk for recurrent VTE in patients with cancerassociatedthrombosis should include all cancer types anddissemination status. Further studies evaluating the benefitand risk of specific anticoagulant strategies according to theprimary cancer site are warranted.