Primary Thromboprophylaxis for Cancer Outpatients on Chemotherapy : Case study

1. PrimaryThromboprophylaxisforCancerOutpatientsonChemotherapy:Case study Carme Font, MD Medical OncologyDepartment Barcelona Spain

2. Primary Thromboprophylaxis in Cancer

3. Primary Thromboprophylaxis in Cancer Khorana et al. Cancer 2013

4. EmergencyRoom 2nd October, 2015 68-yr-old male Acute-onset severediffuse abdominal crampingpainwith heavy biliousvomiting • PractisingStomatologist. • Active smoker. • Overweight: 1,73 m 93 Kg BMI 31 Kg/m2 • Arterial hypertension -> Enalapril • Diabetes Mellitus -> Metformin • Chronicconstipation.

5. EmergencyRoom 2nd October, 2015 68-yr-old male Acute-onset severediffuse abdominal crampingpainwith heavy biliousvomiting • PractisingStomatologist. • Active smoker. • Overweight: 1,73 m 93 Kg BMI 31 Kg/m2 • Arterial hypertension -> Enalapril • Diabetes Mellitus -> Metformin • Chronicconstipation.

6. EmergencyRoom 2nd October, 2015 68-yr-old male Acute-onset severediffuse abdominal crampingpainwith heavy biliousvomiting Blood test: 15.6 gr/dl Hemoglobin 8,820 Leukocytes/mm3 264,000 Platelets/mm3 Liver and renal parameterswithin normal limits Abdominal X-ray: Abnormal air-fluid levels in dilatedsmallbowelloops compatible with intestinal occlusion.

7. EmergencyRoom 2nd October, 2015 Emergency abdominal CT scan: 3 x 3.5 cm transmuralinfiltrativemass compatible withocclusive neoplasia in themiddlethird of thedescending colon. Distension of ilealloops and theascending, transverse and upperthird of descending colon. No signs of disseminationtotheliver, other abdominal structuresincludinglymphnodes. Permeable portal vein. Infrarenalpartiallythrombosedaorticaneurysmof 29 mm in therightcommonilliacartery (35 mm length). In thepartiallyexploredlungparenchyma, a 14 mm paracardiacnodulewasobserved in themiddlelobesuggestive of metastaticlesion in thecontext of thepatient.

8. Hospital Admission -> 3rdOctober, 2015 EmergencyFibrocolonoscopy -> Descending Colon Stenting Bridge-to-Surgery - Toavoidemergencysurgery - Allowpreoperativebowelpreparation • Colono-CT scan: no concomitantlesions in therest of the colon. 7th October, 2015 • Electiveleftlaparoscopic-assistedhemicolectomy. No signs of peritoneal involvement. Postoperativefever -> Prolongued IV antibiotics-> 16 days of hospitalization After hospital discharge: Overall Oral antibiotics + Enoxaparin 40mg/dayfor 10 days-> 26 days LMWH prophylaxis Home nursingsupportfor 7 days 24-hour ER visitforcaringforthesurgicalwound.

9. Hospital Admission -> 3rdOctober, 2015 EmergencyFibrocolonoscopy -> Descending Colon Stenting Bridge-to-Surgery - Toavoidemergencysurgery - Allowpreoperativebowelpreparation • Colono-CT scan: no concomitantlesions in therest of the colon. • Theaneurysmatic aorta and the • cardiovascular riskfactorswereputintothebackgroundbut • notspecificallyaddressed at hospital discharge. 7th October, 2015 • Electiveleftlaparoscopic-assistedhemicolectomy. No signs of peritoneal involvement. Postoperativefever -> Prolongued IV antibiotics-> 16 days of hospitalization After hospital discharge: Overall Oral antibiotics + Enoxaparin 40mg/dayfor 10 days-> 26 days LMWH prophylaxis Home nursingsupportfor 7 days 24-hour ER visitforcaringforthesurgicalwound.

10. Medical OncologyOutpatientClinics Firstvisit13th, November 2015 Good general condition ECOG 0 1,73 m 87 Kg BMI 29 Kg/m2 Hb 12.5 gr/dl Leukocytes 6,530 Platelets 235,000 Glucose 130 mg/dl Final pathologicalReport: 4 cm Adenocarcinoma colonicorigin (splenicangle) High histological grade / Angiolymphatic and perineuralinvasion Free surgicalmargins pT3 N1b (2/16) Mx (undeterminedlungnodule vs. oligometastasis) Discussionwiththepatient and hiswife: - Pros and cons of ‘complementary’ chemotherapy. - PET scan - Port-a-cath

11. 2nd December, 2015 Port-a-cathrightsubclavianvein PET-scan: confirmedmoderateactivity of theparacardiacnodule. • 17th December, 2015 Chemotherapy mFOLFOX-6 scheduledbytelephonecall Continuous 5-FU infusionfor 3 days at home • 26th January, 2016 Pre-C4 FOLFOX • Asthenia G2 ECOG1 • Paresthesia in thehands G1 • 4-day history of edema ontheleftleg • Hemoglobin 11,5 gr/dl CT scan 18th January 2016 (3 cyclesFolfox): • Leukocytes 4,500/mm3 Reductionparacardiacnoduleto 12 mm (prev 14 mm) • Platelets 80,000 No othersigns of cancerdissemination. • Glucose 350 mg/dl Infrarrenalaneurysmatic aorta 35 mm (prev 29 mm) • involvingtheright and leftcommonilliacarteries. •  Chemotherapypostponed  Day Care Hospital

12. PHYSICAL NEEDS • US-Doppler-> Femoral and popliteal DVT -> self-injection LMWH • Insulinduringchemotherapy • Closeplateletcountmonitoring • Referralto a cardiovascular specialist • EDUCATION: • AwarenessaboutPE symptoms • Topreventposthromboticsyndrome • Topromoteregular physicalactivity • EMOTIONAL NEEDS • Knowledge crisis: Stress and concernforbecomingaware of themultiplepotentially ‘life-threatening’ complications: • - VTE • - Aneurysmatic aorta • - Paracardiacnodule • Fearaboutreceiving more chemotherapy (asthenia, parestesia, VTE) • DAY CARE HOSPITAL: • SupportiveCare in Cancer Multidimensional approach • SOCIAL NEEDS • Uncertaintyabouthisfutureprofessionalpractice as stomatologist • Concernabouthowto drive hiscommitmentwithotherprofessionalshired in hisclinics.

13. Theongoingpatient’sjourney … May 2016: completed 11 cycles FOLFOX (Dosereduction) June 2016: CT scanstability of theparacardiacnodule July 2016: CancerCommittee Paracardiacnodulenot accesible for radical treatmentwithradiofrequency August 2016 -> Medial lobesegmentectomywithminimallyinvasivevideothoracoscopy. Final pathological diagnosis: Hamartoma. October 2016 • CT scan: No signs of tumoral activity. • Persistentinfrarrenalaneurysmatic aorta 35 mm withgreaterinvolvement of bothprimitiveilliacarterieswithminimal mural thrombus. • Anticoagulant LMWH interrupted after 9 months -> ASA 100 mg/day December 2016 Aorticbifurcatedprosthesis placed. • June 2017 • No evidence of cancerrelapse • Mildperipheralneuropathy, stillworkspart-time • Minimalposthromboticsymptoms in theleftleg • Quit smoking • Regular physicalactivity 97 Kg BMI 32 Kg/m2

14. Couldithavebeen done bettertoprevent VTE in thispatient?

15. 5.4 American College of ChestPhysicians (ACCP) Guidelines 2012 Canceroutpatientsthromboprophylaxis 4.2.1. In outpatientswithcancerwhohaveno additionalrisk factors for VTE, wesuggestagainstroutineprophylaxiswith LMWH or LDUH (Grade 2B) and recommendagainsttheprophylacticuse of vitamin K antagonists (Grade 1B) . 4.2.2. In outpatientswithsolid tumors whohaveadditionalrisk factors for VTE and whoare at lowrisk of bleeding, wesuggestprophylacticdose LMWH or LDUH over no prophylaxis. 4.4. In outpatientswithcancer and indwelling central venouscatheters, wesuggestagainstroutineprophylaxiswith LMWH or LDUH (Grade 2B) and suggestagainsttheprophylacticuse of vitamin K antagonists (Grade 2C). Additionalrisk factors include: previousvenousthrombosis, immobilization, hormonal therapy, angiogenesisinhibitors, thalidomide, and lenalidomide.

16. American College of ChestPhysicians (ACCP) Guidelines 2012 Canceroutpatientsthromboprophylaxis 4.2.1. In outpatientswithcancerwhohave no additionalrisk factors for VTE, wesuggestagainstroutineprophylaxiswith LMWH or LDUH (Grade 2B) and recommendagainsttheprophylacticuse of vitamin K antagonists (Grade 1B) . 4.2.2. In outpatientswithsolid tumors whohaveadditionalrisk factorsfor VTE and whoare at lowrisk of bleeding, wesuggestprophylacticdose LMWH or LDUHover no prophylaxis. 4.4. In outpatientswithcancer and indwelling central venouscatheters, wesuggestagainstroutineprophylaxiswith LMWH or LDUH (Grade 2B) and suggestagainsttheprophylacticuse of vitamin K antagonists (Grade 2C). Additionalrisk factors include: previousvenousthrombosis, immobilization, hormonal therapy, angiogenesisinhibitors, thalidomide, and lenalidomide. Chemotherapynotincluded !!!

17. PROTECHT Needtotreat 53 patients toavoid 1 arterial orvenousthromboticevent SAVE-ONCO Needtotreat 45 patients toavoid 1 venousthromboticevent NO differences in mortality

18. PROTECHT Needtotreat 53 patients toavoid 1 arterial orvenousthromboticevent SAVE-ONCO Needtotreat 45 patients toavoid 1 venousthromboticevent NO differences in mortality

19. PROTECHT Needtotreat 53 patients toavoid 1 arterial orvenousthromboticevent SAVE-ONCO Needtotreat 45 patients toavoid 1 venousthromboticevent NO differences in mortality

20. Cancer-AssociatedThrombosis: riskfactors

21. N= 17,984

24. Risk-assessmentmodelsdeveloped • topredict VTE in cancerpatients AlokKhorana Ingrid PabingerCihan Ay

25. May - June 2017

28. Score > 2 12-mo probability33.9% Score = 2 12-mo probability19.4% Score = 1 12-mo probability9.7% Score = 0 12-mo probability3.7%

29. Conclusions: • PHARMACOLOGICAL thromboprophylaxis? • Severalrisk-assessmentmodelstoidentifycancer at a highest VTE risk. • Lack of controlledtrialsevaluatingtheefficacy and safety of primarythromboprophylaxisbaseduponthesemodels. • Lack of riskassessmentmodelstopredictbleeding(chemo-inducedrenal insufficiency and thrombocytopenia). • SeveralCancer-, Treatment- and Patient-related VTE-riskfactors -> • Continuousreassessment and Shared-decisionmakingwithpatients / caregivers. • EDUCATION: • Toincrease AWARENESS amongst • HealthProfessionals and Patients. • Early diagnosis of VTE. • VTE prevention: promotingHealthyLifestyles.

30. Thank you ! CFONT@clinic.cat