1. Palliative and supportive care in lung cancer Dr. Răzvan Curcă Emergency County Hospital Alba Iulia, Romania

2. Palliative care (PC) Seeks to manage the symptoms of advanced and terminal illness Views people as a whole individual rather than a disease process to be treated Delivers holistic care through multidisciplinary team working MORE ON THIS SUBJECT ON SUNDAY AT 8:30 A.M.

3. Model of palliative cancer care

4. Main physical problems in advancedlung cancer patients Pain Dyspnea Local airway symptomes: cough, hemoptysis, and postobstructive pneumonia Brain metastases Palliative emergencies- spinal cord compression, superior vena cava syndrome, hypercalcemia Silvestri GA, et. Al: Caring for the Dying Patient With Lung Cancer, Chest, September 2002, 122:1028-1036

5. Comprehensive assesment in PC&SC

6. Ideal therapy in advanced lung cancer Improve overall survival Improve quality of life No or minimal toxicity Nearly all of the recommendations in this guideline are based on clinical trials that demonstrate improvements in OS using chemotherapy, with improvement (or lack of detriment) in QOL. Azzoli, CG, Baker S, Jr, Temin, S, et al. ASCO Clinical Practice Guideline update on chemotherapy for stage IV NSCLC. JClinOncol 2009; 27:6251.

7. Early Palliative Care for Patients withMetastatic Non–Small-Cell Lung Cancer Temel JS, Greer JA, Gallagher E, Admane S, Pirl WF, Jackson VA, Dahlin C, Muzikansky A, Jacobsen J, Lynch TJ

9. Study objectives Primary objective: Change from baseline to 12 weeks in the score on the Trial Outcome Index (TOI), which is the sum of the scores on the lung cancer subscale (LCS) for 7 cardinal symptomes and the physical well-being and functional well-being subscales of the FACT-L QoL scale. Secondary objectives: Mood change from baseline to 12 weeks in the score on Hospital Anxiety and Depression Scale (HADS) and the Patient Health Questionnaire 9 (PHQ- 9) Percentage of patients receiving aggressive end-of-life care (chemotherapy within 14 days before death, no hospice care, or admission to hospice 3 days or less before death) Overall survival

11. There was no difference in the use of antidepressant agents!

12. Effects on end-of-life care Fewer patients in the PC vs. the standard care group received aggressive end-of-life care. Aggressive End of Life Care Standard Care 54% p = .05 Standard Care + PC 33%

13. Less aggressive end-of-life care More resuscitation directives in advance (54% vs. 33%, p = 0.05). Early referral to hospice (median duration of hospice care, 11 vs. 4 days, P = 0.09) Fewer chemotherapy within 14 days before death BUT less aggressive end-of-life care did not adversely affect survival!

16. 1 Center (MassGenH)

17. Relatively Non-Diverse Population

19. NEJM Speaker’s Editorial“Palliative Care — A Shifting Paradigm” Well designed, well-executed study with clinically relevant end points. Early palliative medicine referral improved survival with almost 3 months along with better QOL. Same survival advantage as palliative platinum-based chemotherapy. This study is an example of research that shifts a long-held paradigm that PC is the alternative to life-prolonging or curative care — “what we do when there is nothing more that we can do”— rather than as a simultaneously delivered adjunct to disease-focused treatment. Kelley AS, Meier DE. Palliative Care — A Shifting Paradigm. NEJM 2010; 363:781-782.

20. Early PC in advanced lung cancer    Improved overall survival Improved quality of life No toxicity IN ADDITION TO STANDARD CHEMOTHERAPY!

21. “ There’s not a place in the world where I’ve found people eager to die. If [palliative care] is marketed as end-of-life care, there is the same reluctance; if it’s marketed as a way to have a much better life and help you live longer, then it’s much more acceptable.” Dr. Frank Ferris Director, International Programs, San Diego Hospice & Palliative Care

23. Consequence: defining BSC BSC (best supportive care) is an old term (‘80s), but very familiar to many oncologists It is “politically correct term” used for “no chemo” in clinical trials with chemotherapy vs. no chemotherapy design What is the difference between BSC and SC ??

24. Why was BSC introduced? It’s easier to be accepted by the patients in order to be included in clinical trials with that specific design (“best” is supposed to be better than standard care). It could be more acceptable by ethics comitees and regulatory bodies.

25. BSC - implications Usually, the BSC arm is found to be inferior to the chemotherapy arm with respect to objective tumor response and survival. Possible conclusion: it’s always preferable to receive chemo than to be referred to PC!

26. BSC – future directions After Temel’s study it will be mandatory to define precisely all PC&SC interventions in clinical trials in order to prevent flaws in results. Integration of new assessment instruments frequently used in PC (eg. ESAS). Necessity for defining and implementing quality standards for PC&SC (defining Best).

28. Killing the symptom without killing the patient Maybe the most challenging cases are advanced lung cancer pts. with severe dyspnea The main question: are opioids safe in this clinical setting?

29. Management of dyspnea in advancedlung cancer patients

30. Opioids in the therapy of dyspnea It sounds like “malpraxis” for many oncologists from Balkan countries, because of a restrictive legislation promoting opiophobia among many physicians Lack of proper PC&SC training during medical studies and residency induce also opiophobia (e.g. in Romania- no PC training in almoust all Medicine Universities, only a few months during residency, few PC specialists and trainers) Regulatory barriers in access to opioids

31. European consumtion of morphine

32. Bureaucratic barriers in opioid access The countries with the most limited opioid formularies tended also to have the greatest number of regulatory barriers to accessibility. Among the Western European countries, Turkey and Greece had more limited formularies and more accessibility barriers compared with the other countries. Among the East-European countries, there was much greater heterogeneity. Some countries like the Czech Republic, Croatia and Hungary had formulary availability and accessibility that was as good as most of the Western European countries. In contrast, several countries including Montenegro, Macedonia, Bosnia–Herzegovina, Albania and Ukraine had very restricted formularies and multiple barriers to accessibility. N. I. Cherny, J. Baselga et al. Formulary availability and regulatory barriers to accessibility of opioids for cancer pain in Europe: a report from the ESMO/EAPC Opioid Policy Initiative Ann Oncol 2010: 21(3): 615-626

33. Pivotal trials of opioids for dyspnea Bruera E, MacEachern T, Ripamonti C, et al. Subcutaneous morphine for dyspnea in cancer patients. Ann Intern Med 1993 Mazzocato C, Buclin T, Rapin C-H. The effects of morphine on dyspnea and ventilatory function in elderly patients with advanced cancer: a randomized double-blind controlled trial. Ann Oncol 1999 Allard P, Lamontagne C, Bernard P, et al. How effective are supplementary doses of opioids for dyspnea in terminally ill cancer patients? A randomized continuous sequential clinical trial. J Pain Symptom Manage 1999

34. Opioids in the therapy of dyspnea Studies show that appropriate doses of opioids do not cause respiratory depression. Caution is adviced for pts.: > 65 years During dose titration of the opioid With abnormal renal function With concomitant use of sedatives Close monitoring is very important.

35. Opioids in the therapy of dyspnea Thomas JR, von Gunten CF. Clinical management of dyspnoea. Lancet Oncol 2002;3(4):223-8.

36. Systematic review of medical interventions for cancer-related dyspnea The administration of subcutaneous morphine resulted in a significant reduction in dyspnea Visual Analog Scale (VAS) compared with placebo. No difference was observed in dyspnea VAS score when nebulized morphine was compared with subcutaneous morphine, although patients preferred the nebulized route. Ben-Aharon I, Gafter-Gvili A, et al. Interventions for Alleviating Cancer-Related Dyspnea: A Systematic Review, J Clin Oncol May 10, 2008:2396-2404

37. Role of supplemental oxygen Oxygen was not superior to air for alleviating dyspnea, except for patients with hypoxemia. In PC, the use of supplemental oxygen is expensive and may carry adverse effects including restriction of activities, possible impairment of quality of life, and psychological dependence. Ben-Aharon I, Gafter-Gvili A, et al. Interventions for Alleviating Cancer-Related Dyspnea: A Systematic Review, J Clin Oncol May 10, 2008:2396-2404

38. Role of supplemental oxygen A recent double-blinded randomized clinical trial, published in 2010, confirm the results of the systematic review 239 pts. were randomized between oxygen and room air, administered via nasal cannula Confirms that air movement over the face, nose, and nares helps relieve dyspnea whether it is via nasal cannula, fan, or an open window. Abernethy, AP, McDonald, CF, Frith, PA, et al. Effect of palliative oxygen versus room air in relief of breathlessness in patients with refractory dyspnoea: a double-blind, randomised controlled trial. Lancet 2010; 376:784.

39. Role of benzodiazepines The addition of benzodiazepines to morphine was significantly more effective than morphine alone, without additional adverse effects*. Cochrane review 2010- Benzodiazepines are indicated as a second or third-line treatment, when opioids and non-pharmacological measures have failed to control breathlessness. Main effect is mainly by alleviation of anxiety, frequently asscociated with shortness of breath, which frequently is worsening dyspnea. *Navigante AH, Cerchietti LC, Castro MA, et al: Midazolam as adjunct therapy to morphine in the alleviation of severe dyspnea perception in patients with advanced cancer. J Pain Symptom Manage 31:38-47, 2006

40. Take home messages Early PC & SC in advanced lung cancer pts. led to significant improvements in both quality of life and survival in addition to standard chemotherapy. Defining and implementing quality standards for PC&SC is of paramount importance for future clinical research Mainstay therapy for dyspnea in lung cancer patients are opioids, benzodiazepines and non-pharmacological interventions.

41. Thank You for Your Attention! Aerial view of Alba Iulia Fortress, Romania