CAGPO 2018: Cancer Associated Thrombosis

Transcription

1 CAGPO 2018: Cancer Associated Thrombosis Dr. Marc Carriere (thrombosis) and Dr. Sandy Sehdev (medical oncology) uottawa.ca uottawa.ca Faculté de médecine Faculty of Medicine

2 Objectives To develop a modern understanding of the approach to the treatment of cancer associated thrombosis in the setting of novel cancer treatments newer anticoagulant choices for Rx uottawa.ca uottawa.ca Faculté de médecine Faculty of Medicine

3 Evaluation Were the concepts presented clearly and logically? Do you feel comfortable managing CAT patients in the clinic? uottawa.ca uottawa.ca Faculté de médecine Faculty of Medicine

4 Disclosure: Dr. Sehdev Grants/research support: none Honoraria: Leo advisory board 2014, CAGPO presentation 2018 Consulting fees: none Patents: none Other: travel support for this meeting uottawa.ca uottawa.ca Faculté de médecine Faculty of Medicine

5 Disclosure: Dr. Carrier Grants/research support: BMS, Pfizer and Leo Pharma Honoraria: CAGPO presentation 2018, Bayer, Sanofi, BMS, Servier, Leo Pharma and Pfizer. Consulting fees: Patents: None Other: travel support for this meeting uottawa.ca uottawa.ca Faculté de médecine Faculty of Medicine

6 Mitigating potential bias Neither Leo nor any other industry source has had direct input into the development of our content Only generic names will be used, without logos The evidence basis for recommendations will be highlighted uottawa.ca uottawa.ca Faculté de médecine Faculty of Medicine

7 Overview Overview Risk factors changing dynamic of patient populations Rx factors Disease factors Current guidelines for Rx (guidance statement) Choice of agents LMWH, oral DOACs Practical issues in management bleeding reversal failure thrombocytopenia bridging around procedures drug drug interactions uottawa.ca uottawa.ca Faculté de médecine Faculty of Medicine

8 Changing Landscape in Oncology: Patient Factors Aging demographic Newer Rx: targeted Rx, biologics, immunotherapy allow consideration in older, sicker patients Longer survival / longer time on therapies Comorbidities often on ASA or anticoagulants for cardiac indications Tumoral bleeding risks: CNS mets, in-situ GI/GU malignancies uottawa.ca uottawa.ca Faculté de médecine Faculty of Medicine

9 Changing Landscape in Oncology: Treatment Factors Thrombocytopenia: gemcitabine, carboplatin, T-DM1 More complex protocols: FOLFIRINOX (pancreatic ca), Myeloma: lenalidomide (VTE risk), hyperviscosity Immunotherapies: risk of bleeding from complications (colitis) Multiple new oral targeted Rxs: potential for drug interactions (cytochrome p450, P-glycoprotein, ) uottawa.ca uottawa.ca Faculté de médecine Faculty of Medicine

10 Changing Landscape in Oncology: Clinic Impact Busy! How to handle prophylaxis, acute management of CAT Specialized thrombosis teams not always available Support for home sc injection teaching / administration varies Review of renal function, drug interactions Pt education uottawa.ca uottawa.ca Faculté de médecine Faculty of Medicine

11 Format today: Discussion around a case Lung cancer Stage III PICC DVT issues Bumpy road: Rx and disease complications! Practical discussion around real issues! uottawa.ca uottawa.ca Faculté de médecine Faculty of Medicine

12 CASE PRESENTATION 42 F with cough, SOB pt3n2m0 NSCLC (squamous) of LUL stage IIIa, unresectable Rx: combined modality chemotherapy and radiation PET scans negative elswhere, brain MRI negative Still smoking Otherwise well, no past hx of VTE Rx: Cisplatin and etoposide chemotherapy daily iv x first 5 days and last 5 days of XRT XRT: 60 Gy over 5 weeks Adjuvant durvalumab immunotherapy iv q 2 wk - planned for 12 months PICC line required for iv access

13 CASE PRESENTATION During week 2: swollen R arm (PICC side) U/S confirms proximal arm DVT CBC unremarkable, egfr 65 ml/min Risk factors: obese, sedentary, cancer, smoking, chemo, PICC line Quits smoking! Given 1 dose of LMWH in ER and next day F/U consultation arranged

14 INTERACTIVE QUESTIONS Should we have considered prophylactic anticoagulation before her chemotherapy? 1. Yes 2. No

15 PREVALENCE OF CAT

16 CHEMOTHERAPY FURTHER INCREASES RISK FOR VTE Cumulative risk for VTE in patients with cancer undergoing chemotherapy. Pancreas Stomach Lung All Colon/rectum Ovary Bladder Adapted from Lyman GH, et al. The Oncologist. 2013;18:

17 Adapted from Lyman GH, et al. ASCO Update. J Clin Oncol. 2013;31:

18 HOW COMMON ARE CATHETER-RELATED THROMBOSIS (CRT) CRT represents approximately 70% of all upper extremity DVTs and 10% of all DVTs/PEs Risk factors include: Type of Central Venous Catheters PICC > implanted ports Location (i.e., junction of the superior vena cava and the right atrium) Insertion site femoral > subclavian > jugular Prior history of DVT/PE Metastatic disease Kreuziger LB et al, Thrombosis Research 2017;157:64-71

19 WHEN TO THEY OCCUR? Mean duration from catheter insertion to a CRT diagnosis is 10 days Large majority of CRTs will occur in the initial 100 days following the insertion Kreuziger LB et al, Thrombosis Research 2017;157:64-71

20 Carrier M, et al. J Thromb Haemost. 2007;5: ANTICOAGULATION TO PREVENT CRT?

21 INTERACTIVE QUESTIONS What would you prescribe? 1. LMWH long term tinzaparin, dalteparin, enoxaparin 2. Oral direct oral anticoagulant

22 INITIAL MANAGEMENT OF CRT ISTH Scientific and Standardization Committee guidance Therapeutic dose of anticoagulation without removal of the catheter is recommended if the CVC is functional and required for ongoing therapy If CVC needs to be removed (i.e., non-functioning), a short duration of anticoagulation (3 5 days) prior to removal is recommended Zwicker JI et al, J Thromb Haemost 2014;12:

23 ACUTE AND LONG-TERM TREATMENT OF CRT No comparative studies between anticoagulant agents exist in any population of patients Borrowing from other cancer data, LMWH is typically recommended in those with active cancer Zwicker JI et al, J Thromb Haemost 2014;12: Carrier M, et al. Current Oncology 2015;22(1):49-59.

24 LMWH FOR THE TREATMENT OF CRT Recent retrospective cohort of ~100 patients with CRT and active cancer mostly treated with therapeutic LMWH as per CLOT trial regimens reported the following outcomes: No recurrent events in those on therapeutic LMWH Incidence of major bleeding was 3.7 per 100 patients years (2 required stopping anticoagulation) Delluc A, et al. Thromb Res. 2015;135:

25 DOAC FOR THE TREATMENT OF CRT Catheter-2 study N=70 cancer patients with CRT Rivaroxaban 15 mg PO BID X 21 days then 20 mg PO daily X 3 mo 100% Preservation of line function 1 (1.4%) recurrent CAT Fatal PE 9 (12.5%) patients had 11 bleeding events Davies et al, Thromb Res :88-92.

26 DOAC FOR THE TREATMENT OF CRT Catheter-2 study N=70 cancer patients with CRT Rivaroxaban 15 mg PO BID X 21 days then 20 mg PO daily X 3 mo 100% Preservation of line function 1 (1.4%) recurrent CAT Fatal PE 9 (12.5%) patients had 11 bleeding events Carrier M, et al. Current Oncology 2015;22(1):49-59.

27 What if she was elderly and arthritic, unable to self-inject?

28 What if her egfr was 30 ml/min?

29 RENAL FAILURE INCREASES RISK OFFATAL PE AND FATAL BLEEDING 8 Fatal PE Multivariate Analysis of Risks Fatal Bleed Odds Ratio Monreal M, et al. Am J Med. 2006;119(12): >60 ml/min ml/min <30 ml/min

30 LMWH FOR CAT IN PATIENTS WITH RENAL DYSFUNCTION Variable Treatment Events n/n % Hazard ratio (95% CI) p value CLOT patients with CrCl <60 ml/min VTE (ITT) (N = 162) Major bleeding (N = 161) Dalteparin 2/ VKA 15/ (0.03, 0.65) Dalteparin 7/ VKA 6/ (0.43, 3.83) CATCH patients with CrCl ml/min Variable VTE (ITT) (N = 131) Treatment Events n/n % Hazard ratio (95% CI) Tinzaparin 9/ VKA 9/ (0.38, 2.12) p value NS Major bleeding (N = 131) Tinzaparin 3/ VKA 5/ (0.13, 2.16) NS Woodruff S et al. J Thromb Thrombolysis 2016;42(4): Bauersachs R et al. Thromb Haemost 2018 May;118(5):

31 What if she has moderate daily gross hemoptysis from her tumour?

32 WHAT IF SHE HAD GROSS HEMOPTYSIS? ISTH Scientific and Standardization Committee guidance CVC removal without anticoagulation is only suggested if therapeutic anticoagulation cannot be safely administered due to active risk of haemorrhage On-going bleeding Thrombocytopenic (low platelet count) Close clinical follow-up. Serial US? Zwicker JI et al, J Thromb Haemost 2014;12:

33 INTERACTIVE QUESTIONS Post Rx, her Hb is 86 and PLT 57 (ANC 0.9) No active bleeding noted Should we: 1. Hold anticoagulation until PLT > 100 then resume? 2. Discontinue Rx permanently? 3. Continue?

34 ANTICOAGULATION DURING THROMBOCYTOPENIA Full anticoagulation (DOACs or LMWH) does not pose excessive risk when platelet count remains above 50 x 10 9 /l Factors to consider: 1. Time since index CAT Highest risk of recurrent VTE in initial 3 months 2. Thrombus burden: Massive PE vs. distal DVT 3. Severity of thrombocytopenia (< 50; 20-50; < 20) Samuelson Bannow BT et al. J Thromb Haemost :

35 THROMBOCYTOPENIA (< 1 MONTH) Platelets < 50 X 10 9 /L Able to maintain platelets with transfusion ( 50) Unable to maintain platelets Therapeutic doses < 20 Samuelson Bannow BT et al. J Thromb Haemost : % dose LMWH Hold LMWH

36 THROMBOCYTOPENIA ( 1 MONTH) ISTH SSC suggest reducing the dose of LMWH to 50% of the therapeutic dose or using a prophylactic dose of LMWH in patients with a platelet count of X 10 9 /L ISTH SSC suggest discontinuing anticoagulation in patients with a platelet count of < 20 X 10 9 /L Samuelson Bannow BT et al. J Thromb Haemost. 2018;16:

37 NEXT STEPS Rx completed Anticoagulation continued CBC normalizes 4 wks later Begins durvalumab (via private drug plan): 10 mg/kg iv q 2wk x up to 1 year for consolidation Rx

38 IMMUNOTHERAPY

39 IMMUNOTHERAPY

40 IMMUNOTHERAPY ; ISSUES Risk of colitis / GI bleeding Newer anti PD-1 (nivolumab, pembrolizumab) or PD-L1 antibodies (atezolizumab, durvalumab): risks of diarrhea ~ 20% but grade 3-4 < 5$ ITP rare Pneumonitis, thyroid dysfunction, rash

41 INTERACTIVE QUESTIONS At week 14, develops grade 3 diarrhea and hematochezia Admitted to hospital Anticoagulation held

42 INTERACTIVE QUESTIONS Should we: 1. Stop anticoagulation for now and manage medically? 2. Stop anticoagulation and reverse? 3. Continue anticoagulation given importance? 4. Stop anticoagulation permanently and d/c PICC?

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44 MANAGEMENT OF BLEEDING Identify and stop all oral anticoagulants, parenteral anticoagulants and antiplatelet agents. Identify source of bleeding (if not already done) Supportive measures (Volume replacement and blood products as needed) to maintain hemodynamic stability and urine output. Consider tranaxemic acid (1 g IV)

45 thrombosiscanada.ca ON-LINE TOOL

46 COLITIS Started on methylprednisolone 1 mg/kg iv q12h, iv hydration Still diarrhea 8/d, watery and bloody Anticoagulation discontinued GI consulted: colonoscopy, biopsy = inflammatory colitis On day 3, infliximab given iv Diarrhea and bleeding resolved, oral prednisone 50 mg/d and tapered over 6 weeks

47 FOLLOW UP Rx discontinued, anticoagulation d/c d after PICC out Post Rx CT = response in tumour, resolved nodes but primary still 2.3 cm F/U CT at 3 mos = new bone (ribs, T6, L3, iliac crest) and liver mets (4, up to 3 cm) Started on chemotherapy with carboplatin (AUC 5) d1 and gemcitabine 1000 mg/m 2 on d1,d8 q 3 wk, palliative intent No further plans for immunotherapy Cycle 2b new 2+ L leg swelling extensive proximal leg DVT confirmed on doppler U/S no further hemoptysis or GI bleeding

48 INTERACTIVE QUESTIONS Choice of Rx? 1. LMWH agent for 6 mos? 2. LMWH indefinitely? 3. Oral DOAC for 6 mos? 4. Oral DOAC indefinitely?

49 Raskob et al. N Engl J Med 2018 Feb 15;378(7): HOKUSAI VTE - CANCER STUDY DESIGN

50 Raskob et al. N Engl J Med 2018 Feb 15;378(7): TIME TO VTE OR MAJOR BLEEDING

51 COMPONENTS OF PRIMARY OUTCOME Recurrent VTE Major Bleeding Event-free Survival E 7.9% vs D 11.3% E 6.9% vs D 4.0% E 55.0% vs D 56.5% HR 0.71 ( ) HR 1.77 ( ) HR 0.93 ( ) p = 0.09 p = 0.04 p = NS

52 TIME to VTE or Major bleeding Edoxaban (N = 522) Dalteparin (N = 524) Hazard Ratio (95% CI) Major bleeding 36 (6.9%) 21 (4.0%) 1.77( ) Fatal 0 2 ICH 2 4 Upper GI 17 3 Lower GI 3 3

53 Kraaijpoel N et al Thromb Haemost. 2018;118: MAJOR BLEEDING COURSE

54 Kraaijpoel N et al Thromb Haemost. 2018;118: CLINICALLY RELEVANT NON MAJOR BLEEDING

55 Kraaijpoel N et al Thromb Haemost. 2018;118: CLINICALLY RELEVANT NON MAJOR BLEEDING

56 Carrier M et al. Current Oncol ACUTE AND LONG-TERM TREATMENT OF CAT

57 Patient is on multiple other drugs: Importance of drug interactions? Practicalities of assessment, pharmacy review Multiple new oral targeted Rxs: potential for drug interactions (cytochrome p450, P-glycoprotein, ) uottawa.ca uottawa.ca Faculté de médecine Faculty of Medicine

58 DRUG-DRUG INTERACTIONS DOACs and warfarin are substrates of key metabolic and transport pathways. Anticoagulant CYP3A4 (metabolic) P-gp (transport) Other CYP metabolizing enzymes (2C9, 2C19, 2C8, 2C18, 1A2) LMWH No No No VKA Major No/Minor All (Major: CYP2C9) Apixaban Major Major Minor: 1A2, 2C8, 2C9, 2C19 Edoxaban Minor Major No Rivaroxaban Major Major No Dabigatran No Moderate No

59 Inhibitors of CYP3A4 and/or P-gp may increase risk of bleeding on DOACs. Chemotherapies CYP3A4 P-gp Doxurubicin Topotecan Vinblastine Mitotane Venetoclax Supportive care CYP3A4 P-gp Aprepitant Methylprednisolone Dexamethasone DRUG-DRUG INTERACTIONS Kinase inhibitors CYP3A4 P-gp Afatinib Alectinib Ceritinib Crizotinib Dasatinib Ibrutinib Idelalisib Imatinib Lapatinib Nilotinib Osimertinib Vemurafenib Lenvatinib

60 After cycle 3b, doppler and physical exam confirm more extensive DVT Asymptomatic segmental PE RLL noted on CT FOLLOW UP

61 INTERACTIVE QUESTIONS Given failure of anticoagulation: 1. Raise dose? 2. Change anticoagulation for DOAC (if started on LMWH) or LMWH (if started on DOAC)? 3. Continue same dose and same type of anticoagulation and hope for the best? 4. Add anti platelet agent (ASA or clopidogrel)?

62 RECURRENT CAT DESPITE ANTICOAGULATION Antithrombotic Therapy for VTE Disease: CHEST Guidelines In patients who have recurrent VTE on long-term LMWH (and are believed to be compliant), we suggest increasing the dose of LMWH by about one-quarter to one-third (Grade 2C). Kearon C, et al. Chest Feb;149(2):

63 RECURENT CAT DESPITE ANTICOAGULATION Antithrombotic Therapy for VTE Disease: CHEST Guidelines In patients who have recurrent VTE on VKA therapy (in the therapeutic range) or on dabigatran, rivaroxaban, apixaban, or edoxaban (and are believed to be compliant), we suggest switching to treatment with LMWH at least temporarily (Grade 2C). Kearon C, et al. Chest Feb;149(2):

64 RECURRENT CAT DESPITE ANTICOAGULATION Ihaddadene et al Carrier et al Sample Recurrent VTE Major bleeding 7.3% 95% CI: % 5.5% 95% CI: % 8.6% 95% CI: % 4.3% 95% CI: % Ihaddadene R, et al. Thromb Res. 2014;134(1):93-5; Carrier M, et al. J Thromb Haemost. 2009;7(5):

65 212 patients with recurrent cancer-associated thrombosis despite anticoagulation followed for 3 months 70% LMWH; 30% VKA. Acute phase: RECURRENT CAT DESPITE ANTICOAGULATION 25% switched anticoagulant (VKA LMWH) 31% dose escalation and 25% same dose Overall risk of recurrent VTE 11% (3 months) risk of recurrent VTE: dose escalation vs. same dose Schulman S, et al. J Thromb Haemost. 2015;13:

66 RECURRENT CAT DESPITE ANTICOAGULATION

67 CANCER RX After cycle 4b chemotherapy: Partial response noted, all liver mets smaller (up to 2.1 cm), bones unchanged but pain improved and ALKP normalized Brain MRI on restaging = 3 new brain mets: 1 cerebellar 1.2 cm and 2 cerebral (up to 2 cm with mild edema, mildly hemorrhagic) Stereotactic XRT planned to CNS mets PLT now 47, Hb 92, ANC 1.2, egfr 50 ml/min

68 INTERACTIVE QUESTIONS Now what to do? 1. D/C anticoagulant and place IVC umbrella filter 2. LMWH indefinitely? 3. Oral DOAC for 6 mos? 4. Oral DOAC indefinitely?

69 RISK of ICH Zwicker JI, et al. J Thromb Haemost. 2016;14(9): OR: 1.07 (95% CI , P=0.81)

70 IVC FILTERS PREPIC 1: Permanent filters and anticoagulation N= 400 PE; DVT; survival PREPIC 2: Temporary filters and anticoagulation N= 398 PE; DVT; survival; bleeding PREPIC Study Group. Circulation 2005;112:416-22; Mismetti P, et al. JAMA. 2015;313(16):

71 IVC FILTERS Large California database (N= CAT) 2747 IVC filters (19.6%) Survival: HR: 1.13 (95% CI: ) DVT: HR: 2.1 (95% CI: ) PE: HR: 0.81 (95% CI: ) Subgroup analyses Bleeding cancer patients: HR: 0.99 (95% CI: ) Wun T, et al. Thromb Res 2016;140S1:S66-S70.

72 Cumulative Incidence* of PE (%) 21% of patients with IVCF had a strong contraindication to anticoagulation (bleeding or major surgery) No benefit for 30-day mortality and no reduction in subsequent PE (+/-DVT) 60% increased risk of recurrent DVT and 20% increased risk of subsequent bleeding when an IVCF was placed 10, 8, 6, 4, 2, 0, Recurrent PE 0,3,0167 6,0333 9,05 12, , ,1 21, , ,15 30, ,1834 Months Cumulative Incidence* of DVT (%) 10, 8, 6, 4, 2, 0, IVCF Recurrent DVT No IVCF 0,3,0167 6,0333 9,05 12, , ,1 21, , ,15 30, ,1834 Months Cumulative Incidence* of Subsequent Bleeding (%) Wun T. ICTHIC PL-27; adapted from Brunson A, et al. Thromb Res Apr;140 Suppl 1:S , 18, 16, 14, 12, 10, 8, 6, 4, 2, 0, IVC FILTERS Subsequent Bleeding 0,3,0167 6,0333 9,05 12, , ,1 21, , ,15 30, ,1834 Months

73 IVC FILTERS ISTH Scientific and Standardization Committee guidance Recommend against IVC filter insertion in the absence of contraindications to anticoagulation Suggest IVC filter insertion in cancer patients with contraindications to anticoagulation and a high risk of potentially fatal PE Recommend resuming anticoagulation with LMWH and removing the retrievable filter in cancer patients when the contraindication has resolved Carrier M, et al. J Thromb Haemost Jan;12(1):116-7.

74 Evaluation Were the concepts presented clearly and logically? Do you feel comfortable managing CAT patients in the clinic? uottawa.ca uottawa.ca Faculté de médecine Faculty of Medicine

75 CAGPO 2018: Cancer Associated Thrombosis THANK YOU! Dr. Marc Carriere (thrombosis) and Dr. Sandy Sehdev (medical oncology) uottawa.ca uottawa.ca Faculté de médecine Faculty of Medicine