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  1. Looking at Breakthrough Nausea/Vomiting andCancer-Related PainThe Cannabinoid Experience Vincent Maida, MD Assistant Professor University of TorontoDivision of Palliative MedicineWilliam Osler Health Centre Toronto, Ontario, Canada

  2. Incidence of Chemotherapy-Induced Nausea and Vomiting (CINV) and Pain in Cancer Patients • Approximately 70%–80% of chemotherapy patients experience nausea and vomiting1 • Patients rank nausea and vomiting as 2 of the most feared side effects of cancer treatment • More than three quarters of cancer patients experience chronic pain during the course of their disease2 1. Wiser W, Berger A. Oncology. 2005;19:637. 2. Portenoy RK. Semin Oncol. 1995;22(suppl 3):112.

  3. Consequences of Unresolved CINV Adverse sequelae of nausea and vomiting in the cancer patient • Serious metabolic derangements • Nutritional depletion and anorexia • Esophageal tears • Wound dehiscence • Deterioration of patients’ physical and mental status • Degeneration of self-care and functional ability • Discontinuation of therapy NCCN Practice Guidelines in Oncology–Version 1. 2007. Antiemesis, MS-1.

  4. CINV—Decreased Quality of Life • FLIE Questionnaire • HEC-FLIE > MEC-FLIE P = .0049 • FLIE-nausea > FLIE-Vomiting P = .0097 • There is a greater negative impact onQOL from nausea than there is from vomiting FLIE = Functional Living Index-Emesis; HEC = highly emetogenic chemotherapy; MEC = moderately emetogenic chemotherapy. Bloechl-Daum, B, et al. J Clin Oncol. 2006;24:4472.

  5. NCCN Practice Guidelines Prechemotherapy Emesis Prevention • Highly emetogenic regimens • Day 1: aprepitant, dexamethasone, and a 5-HT3 antagonist+/- lorazepam • May be modified on days 2–4 • Moderately emetogenic regimens • Day 1: dexamethasone and a 5-HT3 antagonist +/- lorazepam (aprepitant added with select moderately emetogenic regimens) • Modified on days 2–4 • Low emetogenic regimens • Dexamethasone, proclorperazine, or metoclopramide +/- lorazepam NCCN Practice Guidelines in Oncology – Version 1. 2007. Antiemesis, MS-1.

  6. NCCN Practice Guidelines Postchemotherapy/Delayed Emesis Prevention • Highly emetogenic regimens • Primary antiemetic regimen continued through period when delayed emesis may occur (ie, 2–3 days after chemotherapy cycle) • Moderately emetogenic regimens • Dependent upon the antiemetic used before chemotherapy • Palonosetron on day 1 only • Aprepitant continued on days 2 and 3 +/- dexamethasone or lorazepam • Dexamethasone or a 5-HT3 antagonist +/- lorazepam NCCN Practice Guidelines in Oncology – Version 1. 2007. Antiemesis, MS-1.

  7. NCCN Practice GuidelinesBreakthrough Treatment • Around-the-clock administration, rather than PRN dosing, should be considered • Additional agents should be from a different drug class than initial therapy • Possibilities include: dopamine antagonists, metoclopramide, butyrophenones, cannabinoids, corticosteroids, or agents such as lorazepam • Nabilone (cannabinoid) has recently been approved for nausea/vomiting in patients who have not responded to conventional antiemetics NCCN Practice Guidelines in Oncology – Version 1. 2007. Antiemesis, MS-1.

  8. Botanical Marijuana Hashish Endogenous Anandamide 2-AG PEA Cannabinoids • Pharmaceutical • Nabilone • Dronabinol • Delta-9-THC & cannabidiol

  9. CB1—neuromodulation Basal ganglia Hippocampus Cerebral cortex Cerebellum Spinal cord Afferent nociceptors CB2—immunomodulation Spleen Tonsil Mast cells Macrophages Lymphocytes Microglia Cannabinoid Receptors Kalant H. Pain Res Manag. 2001;6:80.

  10. Mechanism of Action of the Cannabinoids 5 EXOGENOUS Cannabinoid Therapy Neurotransmitter (NT) from presynaptic neuron activates the postsynaptic neuron 1 Activated postsynaptic neuron releases endocannabinoids 2 PresynapticNeuron Inhibition ofNeurotransmitterRelease CB1 Receptor 4 Endogenous CB1 ligand diffuses back to and binds to the presynaptic CB1 receptor 3 1 PostsynapticNeuron Endogenous CannabinoidRetrograde Signaling CB1 receptor activates a G-protein, leading to inhibition of NT release 4 3 2 NeurotransmitterReceptor Nabilone is thought to activate CB1 receptors directly, mimicking the effects of endocannabinoids 5 Endogenous and ExogenousCannabinoids Reduce Neuronal Signaling Adapted from Page 5 of Slatkin NE. J Support Oncol. 2007;5(suppl3):1.Reprinted with permission.

  11. Cannabinoids—Supportive Oncology • Established roles • CINV • Emerging roles • Analgesia • Spasmolysis • Anorexia-cachexia • Sedative • Antidepressant • Antineoplastic

  12. Causes of Nausea and Vomiting in Cancer Patients • Gastric stasis • Drugs • Opioids • Chemotherapy • Biochemical • Hypercalcemia • Uremia • Raised intracranial pressure • Intestinal obstruction • Pain Twycross R. Palliative Care. 3rd ed, Radcliffe Medical Press. Oxford:1999:114.

  13. Diverse Neurotransmitters Mediate Emesis Dopamine(D2) Serotonin (5-HT3) Histamine Substance P (NK-1) Endorphins N + V REFLEX GABA Acetylcholine Cannabinoids Drug classes FDA approved in CINV Adapted from Andrews PL, Naylor RJ, Joss RA. Supportive Care Cancer. 1998;6:197-203.

  14. Delayed CINV Is More Prevalent Than Acute CINV • Delayed emesis is 2.5 times more prevalent than acute emesis • For moderately emetogenic chemotherapy • Delayed nausea exceeds acute nausea by 16% • Delayed emesis exceeds acute emesis by 15% • For highly emetogenic chemotherapy • Delayed nausea exceeds acute nausea by 27% • Delayed emesis exceeds acute emesis by 38% Grunberg SM, et al. Cancer. 2004;100:2261.

  15. 5-HT3 Antagonists Are Ineffective for Controlling Delayed CINV in a Substantial Proportion of Patients • 360 patients at 18 private medical oncology groups were enrolled in the study • 322 completed requirements for chemotherapy cycle 1 • Antiemetic regimen • Day 1 30-min prechemotherapy: ondansetron (24 mg PO or 20 mg IV) + dexamethasone (12 mg PO or 10 mg IV) • Remaining days of chemotherapy:regimen that comprised standard care at each practice site Mild nausea Moderate nausea Severe nausea 41 Emesis 38 40 34 35 30 25 25 24 25 23 21 Patients with Delayed Nausea/Vomiting (%) 19 20 17 17 15 10 10 5 0 Carboplatin Cisplatin Doxorubicin Hickok JT, et al. Cancer. 2003;97:2880.

  16. Palonosetron Improves Outcomes, Yet CINV Persists in Most Patients 100 90 80 66 70 58 60 % of Patients Who Failed to Achieve Endpoint (Days 1–5) 49 50 40 30 20 10 0 No Emetic Episode No Rescue Medication No Nausea* Endpoint *Moderate or severe Brames MJ, et al. Presented at the MASCC/ISOO 18th International Symposium; June 22-24, 2006: Toronto, Canada. Reprinted with permission.

  17. Aprepitant Improves Outcomes, Yet CINV Persists in Most Patients 70 Aprepitant Standard therapy 59 56 60 50 44* 39* 40 35 % of Patients inWhom CINV Persisted 30 20* 20 10 0 Acute CINV Delayed CINV Overall *P >.001 compared with standard therapy. Poli-Bigelli S, et al. Cancer. 2003;97:3090.

  18. Anticipatory Nausea and Vomiting • Anticipatory nausea occurs in 29% of chemotherapy patients1,2 • Anticipatory vomiting occurs in 11% of chemotherapy patients1,2 • Anticipatory nausea and vomiting • Mostly on the basis of classic or Pavlovian conditioning3 1. Roscoe JA, et al. J Pain Symptom Manage. 2000;20:113. 2. Morrow GR, et al. Support Care Cancer. 1998;6:244. 3. Reesal RT, et al. Can J Psychiatr. 1990;35:80.

  19. Cannabinoids for the Treatment of CINV—Distinct Therapeutic Mechanism • Combining agents with different mechanisms of action (MOAs) may be the optimal approach to management of CINV1 • Cannabinoids have an MOA different from conventional antiemetics (eg, 5-HT3 or D2 receptor antagonists)1-3 • The antiemetic effect of cannabinoids may be due to interaction with the cannabinoid receptor system (ie, CB1 receptors found in neural tissues)4 1. National Cancer Institute. Available at: http://www.meds.com/pdq/supportive_pro.html. Accessed June 13, 2007. 2. Tramer MR, et al. BMJ. 2001;323:16. 3. NCCN Practice Guidelines in Oncology. 2005;1. Antiemesis. 4. CesametTM (nabilone). Product Information. San Diego, CA: Valeant Pharmaceuticals North America; 2006.

  20. Control of Nausea and Vomiting Cannabinoids—A Systematic Review* 80 Control (placebo or active) 70 Cannabinoid 66 59 57 57 60 45 43 Event Rate (%) 40 36 20 0 vs Placebo vs Active vs Placebo vs Active Vomiting Nausea *21 randomized, comparative studies of cannabinoids with placebo or other antiemetics (oral nabilone, oral dronabinol, intramuscular levonatrodol.) Active control = prochlorperazine, metoclopramide, chlorpromazine, haloperidol, domperidone,and alizapride. Tramer MR, et al. BMJ. 2001;323:16.

  21. Patients’ Rating Preference for Cannabinoids Preference for cannabinoids vs placebo (4 studies) vs active control (14 studies) 0.5 1.0 2.0 4.0 6.0 8.0 10.0 Relative risk (95% CI) Favors cannabinoids Active control = prochlorperazine, metoclopramide, chlorpromazine, thiethylperazine, haloperidol, domperidone, and alizapride. Tramèr MR, et al. BMJ. 2001;323:16.

  22. Etiology of Pain in Breast Cancer Patients • Iatrogenic • Postmastectomy syndrome • Chemotherapy-induced peripheral neuropathy • Taxanes >> vinorelbine > capecitabine • Bone metastases • Neuropathic • Malignant plexopathy • Malignant radiculopathy • MSCC

  23. Cannabinoids—Cancer Pain • European phase III study of a cannabidiol/THC buccal spray1 • N = 177 • Opioid nonresponsive pain • Cannabidiol/THC spray significantly reduced pain compared with placebo(P = .014) • 43% of patients showed >30% improvement in pain (P = .024) 1http://www.dpna.org/1sativex.htm

  24. Cannabinoids in the Treatmentof Other Pain • Chronic, incapacitating back pain1 • Decrease in spinal pain intensity and headache with nabilone • Multiple Sclerosis (MS) neuropathic pain2 • Cannabinoids (cannabidiol/THC buccal spray, cannabidiol, and dronabinol) were significantly superior to placebo in treating neuropathic pain in MS • MS spasticity-related pain3 • Nabilone resulted in a significant decrease in spasticity-related pain 1. Pinsger M, et al. Wien Klin Wochenschr. 2006;118:327. 2. Iskedjian M, et al. Curr Med Res Opin. 2007;23:17. 3. Wissel J, et al. J Neurol. 2006;253:1337.

  25. Rx Cannabinoids—Pharmacokinetics Cesamet® (nabilone). Product Information. Costa Mesa, CA: Valeant Pharmaceuticals; 2006. Marinol® (dronabinol). Product Information. Marietta, GA: Unimed Pharmaceuticals, Inc; 2006.

  26. Cannabinoid Metabolism *Main metabolizing isoenzyme • Metabolized principally through the CYP450 2C9 isoenzyme • No inhibitory or inducing effect on any of the isoenzymes • Competes with very few medications at the metabolic level, including opioids • Examples of medications metabolized by CYP3A4: antifungals, methadone, many antidepressants, HIV protease inhibitors Nahas GG, et al, eds. Marihuana and Medicine. Totowa, NJ: Humana Press; 1999: 74-116.

  27. Aprepitant Metabolism Oral aprepitant 40 mg Weak —125 mg Moderate Weak Inhibitory Effecton OrallyAdministeredCYP3A4 Substrate* Inhibitory Effecton IVAdministeredCYP3A4 Substrate* *Midazolam Majumdar AK, et al. J Clin Pharmacol. 2007;47:744.

  28. Side Effects of Cannabinoids* *If smoked, respiratory effects, such as bronchitis, chronic obstructive pulmonary disease, lung infection. Clark AJ. Pain Res Manage. 2005;10(suppl A):44A.

  29. Summary • Emesis is mediated by a variety of neurotransmitters; thus, full control may require the blocking of multiple brain receptor sites • Current antiemetic agents provide inadequate relief in a substantial number of cancer patients • The mechanism of action of cannabinoids differs from that of conventional antiemetics, making it an appropriate candidate for combination with traditional agents • Cannabinoids have proven to be effective antiemetic adjuvants in patients with uncontrolled nausea/vomiting and can provide additional relief in patients with severe pain • Cannabinoids have demonstrated long-term efficacy and safety

  30. Case Study: Breakthrough CINV with Anthracycline-Based Therapy William J. Gradishar, MD, FACP Director, Breast Medical OncologyNorthwestern UniversityFeinberg School of MedicineRobert H. Lurie Comprehensive Cancer CenterChicago, Illinois

  31. Ms. J • A 44-year-old female presents with a right breast lump, which on physical examination measures ~ 1 cm • A mammogram reveals a suspicious-appearing lesion measuring ~ 1.5 cm in the same area noted on physical exam

  32. Infiltrating Ductal CarcinomaER, PR, and HER2 (-) The patient undergoes lumpectomy and sentinel lymph node biopsy, which confirms the presence of a 1.4 cm infiltrating ductal carcinoma that is ER, PR, and HER2 negative

  33. Sentinel Lymph Node Negativefor Tumor • The sentinel lymph node was negative for tumor • The patient is referred to a medical oncologist for consideration of postoperative systemic adjuvant therapy • Additional planned breast irradiation

  34. Medical Oncologist Assessment The assessment of the medical oncologist is that the patient will benefit from adjuvant chemotherapy, and recommends 4 cycles of doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 (AC)

  35. Discussion with Oncologist • Risk reduction might be expected with this regimen • Expected toxicities • Neutropenia, alopecia, cardiac toxicity, mouth sores, fatigue, and nausea and vomiting

  36. Reassurance and Management The medical oncologist assures the patient that these symptoms canbe prevented or successfully managed should they develop.

  37. AC Regimen and CINV • The doxorubicin/cyclophosphamide (AC) regimen is one of the most commonly recommended regimens for adjuvant therapy of breast cancer, either as a “stand alone” treatment or to be used in conjunction with a taxane (concurrently or sequentially) • Although medical oncologists believe that AC chemotherapy is generally well tolerated by most women, the AC regimen actually falls into the “moderate risk” category (30%–90%) of chemotherapy regimens as it relates to the risk of emesis

  38. AC Regimen and CINV • When patients are carefully questioned regarding symptom control after receiving a chemotherapy regimen such as AC along with standard antiemetics, many (up to 70%) will indicate that emesis is controlled on day 1 after chemotherapy • Only a fraction of patients with well-controlled emesis can decrease to 50% on days 2 and 3 following chemotherapy Hesketh PJ, et al. J Clin Oncol. 2003;21:4112. Poli-Bigelli S, et al. Cancer. 2003;97:3090. Warr DG. J Clin Oncol. 2004;22(suppl): abstr 8007.

  39. Delayed Symptoms Some patients experience delayed symptoms (24 hours or more after chemotherapy), and the risk of nausea and vomiting increases during multiple cycles of therapy

  40. Perception vs Reality in Patients Receiving Moderately or Highly Emetogenic Chemotherapy MD/RN prediction MD/RN prediction Patient experience Patient experience 60 60 50 50 40 40 Patients (%) 30 30 20 20 10 10 0 0 AcuteNausea AcuteVomiting DelayedNausea DelayedVomiting AcuteNausea AcuteVomiting DelayedNausea DelayedVomiting Moderately EmetogenicChemotherapy Highly EmetogenicChemotherapy Schwartzberg L. J Support Oncol. 2006;4(suppl 1):3.

  41. Prevention of Emesis in Women on Day 1 After ChemotherapyResults with Standard Therapy in Randomized Trials All patients received dexamethasone and ondansetron 100 A C 80 6 9 6 6 C i s p l a t i n 60 Patients (%) 40 20 0 Cisplatin group (N = 438): all received cisplatin >70 mg/m2 . Anthracycline/cyclophosphamide group (N = 424): 99% received AC. AC = doxorubicine/cyclophosphamide. Hesketh PJ, et al. J Clin Oncol. 2003;21:4112. Poli-Bigelli S, et al. Cancer. 2003;97:3090. Warr DG. J Clin Oncol. 2004;22(suppl): abstr 8007.

  42. Prevention of Emesis in Womenon Days 2 and 3Results with Standard Therapy in Randomized Trials On Days 2 and 3: Cisplatin patients given dexamethasone 8 mg bid AC patients given ondansetron 8 mg bid 100 A C 80 C i s p l a t i n 60 Patients (%) 4 9 4 7 40 20 0 Cisplatin group (N = 438): all received cisplatin >70 mg/m2 . Anthracycline/cyclophosphamide group (N = 424): 99% received AC. AC = doxorubicine/cyclophosphamide. Hesketh PJ, et al. J Clin Oncol. 2003;21:4112. Poli-Bigelli S, et al. Cancer. 2003;97:3090. Warr DG. J Clin Oncol. 2004;22(suppl): abstr 8007.

  43. Breakthrough CINV In this 44-year-old woman with breast cancer receiving AC adjuvant therapy, breakthrough nausea/vomiting developed despite antiemetic prophylaxis given according to the NCCN guidelines

  44. Options for Breakthrough CINV • Additional agents should be from a different drug class than initial therapy • Possible options include dopamine antagonists, metoclopramide, butyrophenones, cannabinoids, corticosteroids, or agents such as lorazepam NCCN Practice Guidelines in Oncology – Version 1. 2007. Antiemesis, MS-1.

  45. Additional Treatment • Options for breakthrough treatment were discussed with the patient • Dexamethasone + lorazepam were added to her antiemetic regimen

  46. Take-Home Messages • Many patients receive adjuvant chemotherapy, particularly those with small node negative breast cancers, for an acknowledged small potential benefit (reduction in risk of recurrence) • It is incumbent upon oncologists to deliver adjuvant chemotherapy with as few side effects as possible • A substantial portion of patients receiving common regimens such as AC experience CINV despite recommended emetic therapy • There are a variety of options available for the treatment of breakthrough CINV, these include dopamine antagonists, metoclopramide, butyrophenones, cannabinoids, corticosteroids, or agents such as lorazepam

  47. Case Study: Anticipatory CINVand Opioid-Refractory Pain Judith A. Luce, MD Clinical Professor of Medicine, University of California, San Francisco Director, Oncology ServicesSan Francisco General HospitalSan Francisco, California

  48. Ms. F • Ms. F is a 50-year-old Honduran woman who was diagnosed with stage II breast cancer 3 years ago • She had been treated with mastectomy, chest wall radiation therapy, 6 cycles of FEC-75 chemotherapy, and tamoxifen • She came to our hospital with an enlarging mass in her sternum and severe pain

  49. Ms. F • Incisional biopsy was performed because of a lack of information from Honduras—the mass was metastatic triple-negative breast cancer • Staging revealed 2 other osseous metastases, right neck nodes, and no visceral disease • Radiation therapy to the sternal mass was delivered, ultimately helping to reduce pain • Patient was started on short-acting opioids and nonsteroidal anti-inflammatory drug (NSAID) orally, but said the NSAID irritated her stomach

  50. Ms. F • Ms. F returns to clinic having lost 2 kilograms, complaining of insomnia, anorexia, terrible pain, nausea, and fatigue. She is tearful and depressed. She spends most of her time on the sofa or in bed • Opioids are increased, long-acting opioid prescribed, and sertralene and prochlorperazine given • Chemotherapy with weekly paclitaxel and bevacizumab is begun