Gaetano Lanzetta Oncologia Medica INI- Grottaferrata (RM )

1. NEW PHARMACOLOGICAL APPROACHES IN SUPPORTIVE CARE Gaetano Lanzetta Oncologia Medica INI- Grottaferrata (RM )

4. BONE METASTASES Supportive care OBIETTIVI TERAPEUTICI OBIETTIVI TERAPEUTICI MANAGE COMPLICATIONS PREVENT COMPLICATIONS PATIENTS

5. “ What is not measured is not managed “ The "measurement" of the symptom is indispensable for setting up a proper treatment to evaluate its effectiveness, to vary it depending on the individual response. TIME RELATIONSHIP LISTENING Caraceni A. Evaluation and assessment of cancer pain and cancer pain treatment. Acta Anaesthesiol Scand. 2001; 45:1067-75

7. PATIENT REPORTED OUTCOME AND PHYSICIAN ASSESSED TOXICITIES MEASUREMENT

8. PATIENT REPORTED OUTCOME AND PHYSICIAN ASSESSED TOXICITIES PROs offer opportunity for labeling claims and are tools for comparative effectiveness Towards the development of a PRO version of the CTCAE MEASUREMENT

9. MUCOSITIS • CINV • OPIOID INDUCED COSTIPATION • IMMUNE CHECKPOINT INHIBITOR

10. MUCOSITIS • CINV • COSTIPATION • IMMUNECHECKPOINT INHIBITOR • END OF LIFE

11. MUCOSITIS

13. IDENTIFY PATIENT’S RISK

14. MUCOSITIS Nonzee N, Cancer 2008

16. MUCOSITIS Lalla et al. Cancer 2014

18. MUCOSITIS A New Standard of Care for Stomatitis? The SWISH trial showed that concomitant daily use of dexamethasone mouth rinse was well tolerated and significantly lowered the incidence of stomatitis in postmenopausal women receiving everolimus and exemestane for the treatment of hormone receptor–positive metastatic breast cancer. For patients in the SWISH trial, the incidence of grade 2 or higher stomatitis at 8 weeks was 2.4%, compared with 33% in BOLERO-2 (historical control). The mouthwash could be a new standard of care for stomatitis in this patient population and may potentially be used across disease subsets. Volume 18, No. 5, p654–662, May 2017

19. MUCOSITIS Intervention: phase II TD fentanyl Study population:painful mucositis (NRS > 4), esophageal cancer in RT/CT Outcome:change in pain before/after Intervention:standard pain control (SPC: acetaminophen + opioids) vs SPC and gabapentin 900 mg/day Study population: H&N cancer pts receiving RTCT Outcome:maximum VAS during RTCT, use of opioids, QoL

20. - INTERVENTION: RCT glutamine or placebo 3 times/day - STUDY POPOLATION: H&N cancer patients receving RT+CHT - OUTCOME: OM by NCI CTCAE 3.0

21. MUCOSITIS • INTERVENTION: Morphine mouthwhashes vs magic (magnesium aluminium hydroxide,viscous lidocaine and diphenhydramine ) - STUDY POPOLATION: H&N cancer patients receiving RTCT with OM G3 - OUTCOME: OM grade, pain pt satisfaction with Tx

22. MUCOSITIS Morphine and magic mouthwashes are effective inreducing severity of cancer treatment induced oralmucositis in patients with head and neck cancer;however, topical morphine is more effective and results were more satisfactory to patients than the magic mouthwash. More studies with larger sample size and longer follow‑up are required before recommending topical morphine as a routine in the management of oral mucositis. AdvBiomedRes 2015;4:44.

23. BOTH TRIALS WERE POSITIVE ACCORDING TO PHYSICIAN-ASSESSED MUCOSITIS Palifermin significantly reduced the intensity and duration of WHO grade 3 and 4 mucositis in respect to placebo

24. CONCLUSIONS • Multifactorial pathogenesis • Patient reported outcome measurable measure • Oral care is essential, before, during and after therapy • Beware of targeted therapies • Several individual-based interventions (surveys) • Impulse to clinical trials!

25. MUCOSITIS • CINV NAUSEA • COSTIPATION • IMMUNECHECKPOINT INHIBITOR

26. CINV

27. CINV MECHANISMS OF CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING Substance P has a role in CINV both acute and delayed Serotoninreaches peak values ​​6 hours after cisplatin, and within 16 hours it returns to pretreatment levels

28. CINV ACUTE DELAYED

29. CINV

30. STEROID-SPARING 5HT3-RA + NK1-RA OLANZAPINE

31. ARE THEY ALL THE SAME? NEPA 5-HT3 ANTAGONIST NK1-R ANTAGONSIT PALONOSETRON

32. CINV AKYNZEO PIVOTAL STUDY HEC

33. CINV AKYNZEO PIVOTAL STUDY MEC In patients treated with MEC chemotherapy NEPA is statistically more effective than Palonosetron

34. CINV SAFETY - QT

35. CINV Rolapitant 180 mg 1 to 2 hours before HEC administration • Warning- interaction with CYP2D6 substrates • QT prolungation

36. CINV NAUSEA Fosaprepitant 150 mg D1 5HT3RA D1 Dexamethasone 12 mg D1; 8 mg D2-4 Olanzapine 10mg D1-4 Fosaprepitant 150 mg D1 5HT3RA D1 Dexamethasone 12 mg D1; 8 mg D2-4 vs

37. CINV

38. CONCLUSIONS

39. MUCOSITIS • CINV • OPIOD-INDUCED COSTIPATION • IMMUNECHECKPOINT INHIBITOR

40. OPIOID- INDUCED COSTIPATION PAMORA peripherally acting mu opiod receptor antagonist Brock C et al. Drugs. 2012;72:1847-1865; Holzer P. Am J Gastroenterol Suppl. 2014;2:9-16; Poulsen et al Clin Exp Gastroenterology 2014; 7: 345-358 Kalso E et al. Pain. 2004;112:372-380.

41. OPIOID- INDUCED COSTIPATION COSTIPATION

42. OPIOID- INDUCED COSTIPATION Tack J et al. United European Gastroenterology Journal 2015, Vol. 3(5) 471–480

43. OPIOID - INDUCED COSTIPATION Adult patients with OIC and/or LIR • Concentrazione and activity of Naloxegol are increased by the cucncurrent use of CYP3A4 inhibitors and reduced by CYP3A4 inducers OIC: OPIOID-INDUCES COSTIPATION LIR: LAXATIVE INADEGUATE RESPONDER • Patients with symptoms of bowel obstruction • Increased risk of GI perforation • Recurrent or advanced ovarian cancer • Patients treated with VEGF inhibitor. • Children

44. Naloxegol 25 mg /day

45. MUCOSITIS • CINV • COSTIPATION • IMMUNE CHECKPOINT INHIBITORS

46. IMMUNE CHECKPOINT INHIBITORS Anna L Lomax et al., 2017

47. IMMUNE CHECKPOINT INHIBITORS ANTI CTLA4 ANTI PD-1 • More tolerable than anti CTLA4 (Grade 3-4 AES 10-20% vs 20-30% • Thyroid disfuntion • Arthralgias • Myalgias • Vitiligo • Rash • Diarrea • Colitis • Hypophysitis • Pruritus • Hepatotoxicity Trasl Lung cancer res, 2015

48. Management Algorithms Used for Diarrhea/Colitis Following Anti–PD-1 Treatment* Grade 2 Hold treatment Administer supportive care If > 5 days: 0.5-1 mg/kg/day prednisone equivalents followed by taper† Discontinue if: No improvement or symptoms worsen and increase to 1-2 mg/kg/day prednisone equivalents Resume if: AE remains at grade 0/1 after steroid taper *Diarrhea and colitis to varying severity. Grades correspond to NCI CTCAE v4.0. †Consider prophylactic antibiotics. Nivolumab [package insert]. 2016. Postow MA, et al. N Engl J Med. 2015;372:2006-2017.

49. Management Algorithms Used for Diarrhea/Colitis Following Anti–PD-1 Treatment* Grade 3 Grade 4 Hold tx; consider discontinuing Discontinue Consider lower-GI endoscopy 1-2 mg/kg/day prednisone equivalents followed by taper† Discontinue if: If symptoms persist > 3-5 days or recur Add noncorticosteroid immunosuppressive Resume if: AE remains at grade 0/1 after steroid taper *Diarrhea and colitis to varying severity. Grades correspond to NCI CTCAE v4.0. †Add antibiotics; for grade 3, consider hospital admission; for grade 4, hospitalization is recommended.

50. NEW NCCN/ASCO GUIDELINES ON MANAGING IMMUNE-RELATED AES