Vincent Maida, MDVincent Maida, MDAssistant ProfessorAssistant Professor
University of TorontoUniversity of TorontoDivision of Palliative MedicineDivision of Palliative MedicineWilliam Osler Health CentreWilliam Osler Health CentreToronto, Ontario, CanadaToronto, Ontario, Canada
Looking at Breakthrough Looking at Breakthrough Nausea/Vomiting andNausea/Vomiting andCancer-Related PainCancer-Related Pain
The Cannabinoid ExperienceThe Cannabinoid Experience
1. Wiser W, Berger A. Oncology. 2005;19:637.2. Portenoy RK. Semin Oncol. 1995;22(suppl 3):112.
Incidence of Chemotherapy-Induced Incidence of Chemotherapy-Induced Nausea and Vomiting (CINV) and Pain Nausea and Vomiting (CINV) and Pain
in Cancer Patientsin Cancer Patients
Approximately 70%–80% of chemotherapy Approximately 70%–80% of chemotherapy patients experience nausea and vomitingpatients experience nausea and vomiting11
Patients rank nausea and vomiting as 2 of the Patients rank nausea and vomiting as 2 of the most feared side effects of cancer treatment most feared side effects of cancer treatment
More than three quarters of cancer patients More than three quarters of cancer patients experience chronic pain during the course of experience chronic pain during the course of their diseasetheir disease22
NCCN Practice Guidelines in Oncology–Version 1. 2007. Antiemesis, MS-1.
Consequences of Unresolved CINVConsequences of Unresolved CINV
Serious metabolic derangementsSerious metabolic derangements
Nutritional depletion and anorexiaNutritional depletion and anorexia
Esophageal tearsEsophageal tears
Wound dehiscenceWound dehiscence
Deterioration of patients’ physical and mental statusDeterioration of patients’ physical and mental status
Degeneration of self-care and functional abilityDegeneration of self-care and functional ability
Discontinuation of therapyDiscontinuation of therapy
Adverse sequelae of nausea and vomiting in the cancer patient
FLIE = Functional Living Index-Emesis; HEC = highly emetogenic chemotherapy; MEC = moderately emetogenic chemotherapy.Bloechl-Daum, B, et al. J Clin Oncol. 2006;24:4472.
CINV—Decreased Quality of LifeCINV—Decreased Quality of Life
FLIE QuestionnaireFLIE Questionnaire
HEC-FLIE > MEC-FLIE HEC-FLIE > MEC-FLIE PP = .0049 = .0049
FLIE-nausea > FLIE-Vomiting FLIE-nausea > FLIE-Vomiting PP = .0097 = .0097
There is a greater negative impact onThere is a greater negative impact onQOL from nausea than there is from QOL from nausea than there is from vomitingvomiting
NCCN Practice Guidelines in Oncology – Version 1. 2007. Antiemesis, MS-1.
NCCN Practice Guidelines NCCN Practice Guidelines Prechemotherapy Emesis PreventionPrechemotherapy Emesis Prevention
Highly emetogenic regimensHighly emetogenic regimens
– Day 1: aprepitant, dexamethasone, and a 5-HTDay 1: aprepitant, dexamethasone, and a 5-HT33 antagonist antagonist+/- lorazepam+/- lorazepam
– May be modified on days 2–4May be modified on days 2–4
Moderately emetogenic regimensModerately emetogenic regimens
– Day 1: dexamethasone and a 5-HTDay 1: dexamethasone and a 5-HT33 antagonist +/- lorazepam antagonist +/- lorazepam (aprepitant added with select moderately emetogenic regimens)(aprepitant added with select moderately emetogenic regimens)
– Modified on days 2–4Modified on days 2–4
Low emetogenic regimensLow emetogenic regimens
– Dexamethasone, proclorperazine, or metoclopramide Dexamethasone, proclorperazine, or metoclopramide +/- lorazepam+/- lorazepam
NCCN Practice Guidelines in Oncology – Version 1. 2007. Antiemesis, MS-1.
NCCN Practice Guidelines NCCN Practice Guidelines Postchemotherapy/Delayed Emesis PreventionPostchemotherapy/Delayed Emesis Prevention
Highly emetogenic regimensHighly emetogenic regimens
– Primary antiemetic regimen continued through period Primary antiemetic regimen continued through period when delayed emesis may occur when delayed emesis may occur (ie, 2–3 days after chemotherapy cycle)(ie, 2–3 days after chemotherapy cycle)
Moderately emetogenic regimensModerately emetogenic regimens
– Dependent upon the antiemetic used before chemotherapyDependent upon the antiemetic used before chemotherapy Palonosetron on day 1 onlyPalonosetron on day 1 only
Aprepitant continued on days 2 and 3 Aprepitant continued on days 2 and 3 +/- dexamethasone or lorazepam+/- dexamethasone or lorazepam
Dexamethasone or a 5-HTDexamethasone or a 5-HT33 antagonist +/- lorazepam antagonist +/- lorazepam
NCCN Practice Guidelines in Oncology – Version 1. 2007. Antiemesis, MS-1.
NCCN Practice GuidelinesNCCN Practice GuidelinesBreakthrough TreatmentBreakthrough Treatment
Around-the-clock administration, rather than PRN Around-the-clock administration, rather than PRN dosing, should be considereddosing, should be considered
Additional agents should be from a different drug Additional agents should be from a different drug class than initial therapyclass than initial therapy
– Possibilities include: dopamine antagonists, Possibilities include: dopamine antagonists, metoclopramide, butyrophenones, cannabinoids, metoclopramide, butyrophenones, cannabinoids, corticosteroids, or agents such as lorazepamcorticosteroids, or agents such as lorazepam
Nabilone (cannabinoid) has recently been Nabilone (cannabinoid) has recently been approved for nausea/vomiting in patients who approved for nausea/vomiting in patients who have not responded to conventional antiemeticshave not responded to conventional antiemetics
PharmaceuticalPharmaceutical
NabiloneNabilone
DronabinolDronabinol
Delta-9-THC & Delta-9-THC & cannabidiolcannabidiol
CannabinoidsCannabinoids
BotanicalBotanical
MarijuanaMarijuana
HashishHashish
EndogenousEndogenous
AnandamideAnandamide
2-AG2-AG
PEAPEA
Kalant H. Pain Res Manag. 2001;6:80.
Cannabinoid ReceptorsCannabinoid Receptors
CB1—neuromodulationCB1—neuromodulation
Basal gangliaBasal ganglia
HippocampusHippocampus
Cerebral cortexCerebral cortex
CerebellumCerebellum
Spinal cordSpinal cord
Afferent nociceptorsAfferent nociceptors
CB2—immunomodulationCB2—immunomodulation
SpleenSpleen
TonsilTonsil
Mast cellsMast cells
MacrophagesMacrophages
LymphocytesLymphocytes
MicrogliaMicroglia
Mechanism of Action of the CannabinoidsMechanism of Action of the Cannabinoids
Neurotransmitter (NT) from presynaptic neuron activates the postsynaptic neuron
1
2 3
4
5
Endogenous and ExogenousCannabinoids Reduce Neuronal Signaling
PostsynapticNeuron
NeurotransmitterReceptor
Endogenous CannabinoidRetrograde Signaling
CB1 Receptor
PresynapticNeuron
Inhibition ofNeurotransmitter
Release
EXOGENOUS
Cannabinoid Therapy
Activated postsynaptic neuron releases endocannabinoids
Endogenous CB1 ligand diffuses back to and binds to the presynaptic CB1 receptor
CB1 receptor activates a G-protein, leading to inhibition of NT release
Nabilone is thought to activate CB1 receptors directly, mimicking the effects of endocannabinoids
1
2
3
4
5
Adapted from Page 5 of Slatkin NE. J Support Oncol. 2007;5(suppl3):1. Reprinted with permission.
Cannabinoids—Supportive OncologyCannabinoids—Supportive Oncology
Established rolesEstablished roles
– CINVCINV
Emerging rolesEmerging roles
– AnalgesiaAnalgesia
– SpasmolysisSpasmolysis
– Anorexia-cachexiaAnorexia-cachexia
– SedativeSedative
– AntidepressantAntidepressant
– AntineoplasticAntineoplastic
Twycross R. Palliative Care. 3rd ed, Radcliffe Medical Press. Oxford:1999:114.
Causes of Nausea and Vomiting Causes of Nausea and Vomiting in Cancer Patientsin Cancer Patients
Gastric stasisGastric stasis
DrugsDrugs
– OpioidsOpioids
– ChemotherapyChemotherapy
BiochemicalBiochemical
– HypercalcemiaHypercalcemia
– UremiaUremia
Raised intracranial pressureRaised intracranial pressure
Intestinal obstructionIntestinal obstruction
PainPain
Adapted from Andrews PL, Naylor RJ, Joss RA. Supportive Care Cancer. 1998;6:197-203.
Serotonin (5-HT3)
GABA
Cannabinoids
Acetylcholine
Dopamine(D2)
N + V REFLEX
Histamine
Substance P(NK-1)
Endorphins
Drug classes FDA approved in CINV
Diverse Neurotransmitters Mediate EmesisDiverse Neurotransmitters Mediate Emesis
Grunberg SM, et al. Cancer. 2004;100:2261.
Delayed CINV Is More Prevalent Than Delayed CINV Is More Prevalent Than Acute CINVAcute CINV
Delayed emesis is 2.5 times more prevalent Delayed emesis is 2.5 times more prevalent than acute emesisthan acute emesis
For moderately emetogenic chemotherapy For moderately emetogenic chemotherapy
– Delayed Delayed nauseanausea exceeds acute nausea by 16% exceeds acute nausea by 16%
– Delayed Delayed emesisemesis exceeds acute emesis by 15% exceeds acute emesis by 15%
For highly emetogenic chemotherapyFor highly emetogenic chemotherapy
– Delayed Delayed nauseanausea exceeds acute nausea by 27% exceeds acute nausea by 27%
– Delayed Delayed emesisemesis exceeds acute emesis by 38% exceeds acute emesis by 38%
Pat
ien
ts w
ith
Del
ayed
Nau
sea/
Vo
mit
ing
(%
)
5-HT5-HT33 Antagonists Are Ineffective for Antagonists Are Ineffective for Controlling Delayed CINV in a Substantial Controlling Delayed CINV in a Substantial
Proportion of PatientsProportion of Patients
Carboplatin Cisplatin Doxorubicin
360 patients at 18 private medical 360 patients at 18 private medical oncology groups were enrolled in oncology groups were enrolled in the studythe study
– 322 completed requirements for 322 completed requirements for chemotherapy cycle 1chemotherapy cycle 1
Antiemetic regimen Antiemetic regimen
– Day 1 30-min prechemotherapy: Day 1 30-min prechemotherapy: ondansetron (24 mg PO or 20 mg ondansetron (24 mg PO or 20 mg IV) + dexamethasone (12 mg PO or IV) + dexamethasone (12 mg PO or 10 mg IV)10 mg IV)
– Remaining days of chemotherapy:Remaining days of chemotherapy:regimen that comprised standard regimen that comprised standard care at each practice sitecare at each practice site
Hickok JT, et al. Cancer. 2003;97:2880.
Emesis
Moderate nauseaSevere nausea
Mild nausea
40
15
10
5
0
25
20
30
35
21
25
10
23
17
38
19
34
17
41
25 24
Palonosetron Improves Outcomes, Palonosetron Improves Outcomes, Yet CINV Persists in Most PatientsYet CINV Persists in Most Patients
4958
66
0
10
20
30
40
50
60
70
80
90
100
No Emetic Episode No Rescue Medication No Nausea*
Endpoint
% o
f P
atie
nts
Wh
o F
aile
d t
o A
chie
ve
En
dp
oin
t (D
ays
1–5)
*Moderate or severeBrames MJ, et al. Presented at the MASCC/ISOO 18th International Symposium; June 22-24, 2006: Toronto, Canada. Reprinted with permission.
20*
39*44*
35
5659
0
10
20
30
40
50
60
70
Acute CINV Delayed CINV Overall
% o
f P
atie
nts
in
Wh
om
CIN
V P
ersi
sted
Aprepitant
Standard therapy
*P >.001 compared with standard therapy. Poli-Bigelli S, et al. Cancer. 2003;97:3090.
Aprepitant Improves Outcomes, Aprepitant Improves Outcomes, Yet CINV Persists in Most PatientsYet CINV Persists in Most Patients
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.
Anticipatory Nausea and VomitingAnticipatory Nausea and Vomiting
Anticipatory nausea occurs in 29% of Anticipatory nausea occurs in 29% of chemotherapy patientschemotherapy patients1,21,2
Anticipatory vomiting occurs in 11% of Anticipatory vomiting occurs in 11% of chemotherapy patientschemotherapy patients1,21,2
Anticipatory nausea and vomitingAnticipatory nausea and vomiting
– Mostly on the basis of classic or Mostly on the basis of classic or Pavlovian conditioningPavlovian conditioning33
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.
Cannabinoids for the Treatment of CINVCannabinoids for the Treatment of CINV—Distinct Therapeutic Mechanism —Distinct Therapeutic Mechanism
Combining agents with different mechanisms of Combining agents with different mechanisms of action (MOAs) may be the optimal approach to action (MOAs) may be the optimal approach to management of CINVmanagement of CINV11
Cannabinoids have an MOA different from Cannabinoids have an MOA different from conventional antiemetics (eg, 5-HTconventional antiemetics (eg, 5-HT33 or D or D22 receptor receptor antagonists)antagonists)1-31-3
The antiemetic effect of cannabinoids may be due to The antiemetic effect of cannabinoids may be due to interaction with the cannabinoid receptor system (ie, interaction with the cannabinoid receptor system (ie, CB1 receptors found in neural tissues)CB1 receptors found in neural tissues)44
Active control = prochlorperazine, metoclopramide, chlorpromazine, haloperidol, domperidone,and alizapride.
Tramer MR, et al. BMJ. 2001;323:16.
*21 randomized, comparative studies of cannabinoids with placebo or other antiemetics (oral nabilone, oral dronabinol, intramuscular levonatrodol.)
70
57 59
43
66
36
57
45
0
20
40
60
80
CannabinoidControl (placebo or active)
Eve
nt
Rat
e (%
)
vs Placebo vs Active vs Placebo vs Active
Nausea Vomiting
Control of Nausea and Vomiting Control of Nausea and Vomiting Cannabinoids—A Systematic Review*Cannabinoids—A Systematic Review*
0.5 1.0 2.0 4.0 6.0 8.0 10.0Relative risk (95% CI)
Favors cannabinoids
vs placebo (4 studies)
vs active control (14 studies)
Preference for cannabinoids
Active control = prochlorperazine, metoclopramide, chlorpromazine, thiethylperazine, haloperidol, domperidone, and alizapride. Tramèr MR, et al. BMJ. 2001;323:16.
Patients’ Rating Preference for Patients’ Rating Preference for CannabinoidsCannabinoids
Etiology of Pain in Breast Cancer Etiology of Pain in Breast Cancer PatientsPatients
IatrogenicIatrogenic
– Postmastectomy syndromePostmastectomy syndrome
– Chemotherapy-induced peripheral neuropathyChemotherapy-induced peripheral neuropathy Taxanes >> vinorelbine > capecitabineTaxanes >> vinorelbine > capecitabine
Bone metastasesBone metastases
NeuropathicNeuropathic
– Malignant plexopathyMalignant plexopathy
– Malignant radiculopathyMalignant radiculopathy
– MSCCMSCC
Cannabinoids—Cancer PainCannabinoids—Cancer Pain European phase III study of a European phase III study of a
cannabidiol/THC buccal spraycannabidiol/THC buccal spray11
N = 177N = 177
Opioid nonresponsive painOpioid nonresponsive pain
Cannabidiol/THC spray significantly Cannabidiol/THC spray significantly reduced pain compared with placeboreduced pain compared with placebo((P P = .014)= .014)
43% of patients showed >30% 43% of patients showed >30% improvement in pain (improvement in pain (P P = .024)= .024)
1http://www.dpna.org/1sativex.htm
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.
Cannabinoids in the TreatmentCannabinoids in the Treatmentof Other Painof Other Pain
Chronic, incapacitating back painChronic, incapacitating back pain11
– Decrease in spinal pain intensity and headache with Decrease in spinal pain intensity and headache with nabilonenabilone
Multiple Sclerosis (MS) neuropathic painMultiple Sclerosis (MS) neuropathic pain22
– Cannabinoids (cannabidiol/THC buccal spray, cannabidiol, Cannabinoids (cannabidiol/THC buccal spray, cannabidiol,
and dronabinol) were significantly superior to placebo in and dronabinol) were significantly superior to placebo in
treating neuropathic pain in MStreating neuropathic pain in MS
MS spasticity-related painMS spasticity-related pain33
– Nabilone resulted in a significant decrease in spasticity-Nabilone resulted in a significant decrease in spasticity-
related painrelated pain
Cesamet® (nabilone). Product Information. Costa Mesa, CA: Valeant Pharmaceuticals; 2006. Marinol® (dronabinol). Product Information. Marietta, GA: Unimed Pharmaceuticals, Inc; 2006.
RRxx Cannabinoids—Pharmacokinetics Cannabinoids—PharmacokineticsNabilone Dronabinol
Oral dosing 1–2 mg 1–3 h before
chemotherapy, and BID
for up to 48 h afterwards
5 mg/m2 1–3 h before chemotherapy, and
every 2–4 h afterwards for a total of 4–6
doses/d
Source Synthetic ∆9-THC analog Synthetic ∆9-THC
Formulation Crystalline powder
capsule
Capsule formulated with sesame oil, among
other ingredients (contraindicated in patients
with a hypersensitivity to sesame oil)
Onset of action 60–90 min 30–60 min
Peak plasma
concentrations (Tmax)
2 h 2–4 h
Duration of action 8–12 h 4–6 h for psychoactive effects
Metabolites 2 active metabolites 2 active metabolites and >20 other
metabolites
Clearance Major excretory pathway is
the biliary system
Biliary excretion is major route of
elimination
CYP450 Metabolizing Enzymes
CYP450 Enzyme Inhibition
CYP450 Enzyme Induction
Nabilone 2C9*, 3A4(aldehyde oxygenase)
None to date None to date
Dronabinol 2C9*, 2C11, 3A4(aldehyde oxygenase)
3A4 None to date
Nahas GG, et al, eds. Marihuana and Medicine. Totowa, NJ: Humana Press; 1999: 74-116.
Metabolized principally through the CYP450 2C9 isoenzymeMetabolized principally through the CYP450 2C9 isoenzyme No inhibitory or inducing effect on any of the isoenzymesNo inhibitory or inducing effect on any of the isoenzymes Competes with very few medications at the metabolic level, including Competes with very few medications at the metabolic level, including
opioidsopioids Examples of medications metabolized by CYP3A4: antifungals, Examples of medications metabolized by CYP3A4: antifungals,
methadone, many antidepressants, HIV protease inhibitorsmethadone, many antidepressants, HIV protease inhibitors
*Main metabolizing isoenzyme
Cannabinoid MetabolismCannabinoid Metabolism
Aprepitant MetabolismAprepitant Metabolism
Oral aprepitant Oral aprepitant 40 mg40 mg WeakWeak ——125 mg125 mg ModerateModerate WeakWeak
*MidazolamMajumdar AK, et al. J Clin Pharmacol. 2007;47:744.
Inhibitory Effecton Orally
AdministeredCYP3A4 Substrate*
Inhibitory Effecton IV
AdministeredCYP3A4 Substrate*
Symptom/Effect Most Common Common RareCNS Sedation Somnolence Dizziness Euphoria/“high” Blurred vision Anxiety; panic Paranoia Psychosis Depression Ataxia Asthenia Cognitive effects
Cardiovascular Postural hypotension Vasodilatation (red eyes) Tachycardia Palpitations
Others Dry mouth Headache
Clark AJ. Pain Res Manage. 2005;10(suppl A):44A.*If smoked, respiratory effects, such as bronchitis, chronic obstructive pulmonary disease, lung infection.
Side Effects of Cannabinoids*Side Effects of Cannabinoids*
SummarySummary Emesis is mediated by a variety of neurotransmitters; thus, Emesis is mediated by a variety of neurotransmitters; thus,
full control may require the blocking of multiple brain full control may require the blocking of multiple brain receptor sitesreceptor sites
Current antiemetic agents provide inadequate relief in a Current antiemetic agents provide inadequate relief in a substantial number of cancer patientssubstantial number of cancer patients
The mechanism of action of cannabinoids differs from that of The mechanism of action of cannabinoids differs from that of conventional antiemetics, making it an appropriate candidate conventional antiemetics, making it an appropriate candidate for combination with traditional agentsfor combination with traditional agents
Cannabinoids have proven to be effective antiemetic Cannabinoids have proven to be effective antiemetic adjuvants in patients with uncontrolled nausea/vomiting and adjuvants in patients with uncontrolled nausea/vomiting and can provide additional relief in patients with severe paincan provide additional relief in patients with severe pain
Cannabinoids have demonstrated long-term efficacy and Cannabinoids have demonstrated long-term efficacy and safetysafety
Case Study: Breakthrough CINV with Case Study: Breakthrough CINV with Anthracycline-Based TherapyAnthracycline-Based Therapy
William J. Gradishar, MD, FACPWilliam J. Gradishar, MD, FACP
Director, Breast Medical OncologyDirector, Breast Medical OncologyNorthwestern UniversityNorthwestern University
Feinberg School of MedicineFeinberg School of MedicineRobert H. Lurie Comprehensive Cancer CenterRobert H. Lurie Comprehensive Cancer Center
Chicago, IllinoisChicago, Illinois
Ms. JMs. J
A 44-year-old female presents with a A 44-year-old female presents with a right breast lump, which on physical right breast lump, which on physical examination measures ~ 1 cmexamination measures ~ 1 cm
A mammogram reveals a suspicious-A mammogram reveals a suspicious-appearing lesion measuring ~ 1.5 cm in appearing lesion measuring ~ 1.5 cm in the same area noted on physical exam the same area noted on physical exam
Infiltrating Ductal CarcinomaInfiltrating Ductal Carcinoma ER, PR, and HER2 (-)ER, PR, and HER2 (-)
The patient undergoes lumpectomy and The patient undergoes lumpectomy and sentinel lymph node biopsy, which sentinel lymph node biopsy, which confirms the presence of a 1.4 cm confirms the presence of a 1.4 cm infiltrating ductal carcinoma that is ER, infiltrating ductal carcinoma that is ER, PR, and HER2 negative PR, and HER2 negative
Sentinel Lymph Node NegativeSentinel Lymph Node Negativefor Tumorfor Tumor
The sentinel lymph node was negative The sentinel lymph node was negative for tumor for tumor
The patient is referred to a medical The patient is referred to a medical oncologist for consideration of oncologist for consideration of postoperative systemic adjuvant postoperative systemic adjuvant therapytherapy
Additional planned breast irradiationAdditional planned breast irradiation
Medical Oncologist AssessmentMedical Oncologist Assessment
The assessment of the medical The assessment of the medical oncologist is that the patient will oncologist is that the patient will benefit from adjuvant chemotherapy, benefit from adjuvant chemotherapy, and recommends 4 cycles of and recommends 4 cycles of doxorubicin 60 mg/mdoxorubicin 60 mg/m22 and and cyclophosphamide 600 mg/mcyclophosphamide 600 mg/m22 (AC) (AC)
Discussion with OncologistDiscussion with Oncologist
Risk reduction might be expected with Risk reduction might be expected with this regimen this regimen
Expected toxicities Expected toxicities
– Neutropenia, alopecia, cardiac toxicity, Neutropenia, alopecia, cardiac toxicity, mouth sores, fatigue, and nausea and mouth sores, fatigue, and nausea and vomitingvomiting
Reassurance and ManagementReassurance and Management
The medical oncologist assures the The medical oncologist assures the patient that these symptoms canpatient that these symptoms canbe prevented or successfully managed be prevented or successfully managed should they develop. should they develop.
AC Regimen and CINVAC Regimen and CINV The doxorubicin/cyclophosphamide (AC) The doxorubicin/cyclophosphamide (AC)
regimen is one of the most commonly regimen is one of the most commonly recommended regimens for adjuvant therapy of recommended regimens for adjuvant therapy of breast cancer, either as a “stand alone” breast cancer, either as a “stand alone” treatment or to be used in conjunction with a treatment or to be used in conjunction with a taxane (concurrently or sequentially) taxane (concurrently or sequentially)
Although medical oncologists believe that AC Although medical oncologists believe that AC chemotherapy is generally well tolerated by chemotherapy is generally well tolerated by most women, the AC regimen actually falls into most women, the AC regimen actually falls into the “moderate risk” category (30%–90%) of the “moderate risk” category (30%–90%) of chemotherapy regimens as it relates to the risk chemotherapy regimens as it relates to the risk of emesisof emesis
AC Regimen and CINVAC Regimen and CINV
When patients are carefully questioned When patients are carefully questioned regarding symptom control after receiving a regarding symptom control after receiving a chemotherapy regimen such as AC along chemotherapy regimen such as AC along with standard antiemetics, many (up to 70%) with standard antiemetics, many (up to 70%) will indicate that emesis is controlled on day will indicate that emesis is controlled on day 1 after chemotherapy1 after chemotherapy
Only a fraction of patients with well-Only a fraction of patients with well-controlled emesis can decrease to 50% on controlled emesis can decrease to 50% on days 2 and 3 following chemotherapydays 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.
Delayed SymptomsDelayed Symptoms
Some patients experience delayed Some patients experience delayed symptoms (24 hours or more after symptoms (24 hours or more after chemotherapy), and the risk of chemotherapy), and the risk of nausea and vomiting increases nausea and vomiting increases during multiple cycles of therapy during multiple cycles of therapy
Schwartzberg L. J Support Oncol. 2006;4(suppl 1):3.
Perception vs Reality in Patients Receiving Perception vs Reality in Patients Receiving Moderately or Highly Emetogenic Moderately or Highly Emetogenic
ChemotherapyChemotherapy
0
10
20
30
40
50
60
AcuteNausea
AcuteVomiting
DelayedNausea
DelayedVomiting
Pa
tie
nts
(%
)
MD/RN predictionPatient experience
010
2030
40
5060
AcuteNausea
AcuteVomiting
DelayedNausea
DelayedVomiting
MD/RN predictionPatient experience
Moderately EmetogenicChemotherapy
Highly EmetogenicChemotherapy
Cisplatin group (N = 438): all received cisplatin >70 mg/m2 .Anthracycline/cyclophosphamide group (N = 424): 99% received AC.
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.
69 66
AC
Cisplatin
All patients received dexamethasone and ondansetron
100
80
60
40
20
0
AC = doxorubicine/cyclophosphamide.
Prevention of Emesis in Women on Day 1 Prevention of Emesis in Women on Day 1 After ChemotherapyAfter Chemotherapy
Results with Standard Therapy in Randomized TrialsResults with Standard Therapy in Randomized TrialsP
atie
nts
(%
)
49 47
On Days 2 and 3: Cisplatin patients given dexamethasone 8 mg bid AC patients given ondansetron 8 mg bid
Prevention of Emesis in WomenPrevention of Emesis in Womenon Days 2 and 3on Days 2 and 3
Results with Standard Therapy in Randomized TrialsResults with Standard Therapy in Randomized Trials
Cisplatin group (N = 438): all received cisplatin >70 mg/m2 .Anthracycline/cyclophosphamide group (N = 424): 99% received AC.
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.
AC = doxorubicine/cyclophosphamide.
AC
Cisplatin
100
80
60
40
20
0
Pat
ien
ts (
%)
Breakthrough CINVBreakthrough CINV
In this 44-year-old woman with breast In this 44-year-old woman with breast cancer receiving AC adjuvant therapy, cancer receiving AC adjuvant therapy, breakthrough nausea/vomiting breakthrough nausea/vomiting developed despite antiemetic developed despite antiemetic prophylaxis given according to the prophylaxis given according to the NCCN guidelinesNCCN guidelines
Options for Breakthrough CINVOptions for Breakthrough CINV
Additional agents should be from a Additional agents should be from a different drug class than initial therapydifferent drug class than initial therapy
Possible options include dopamine Possible options include dopamine antagonists, metoclopramide, antagonists, metoclopramide, butyrophenones, cannabinoids, butyrophenones, cannabinoids, corticosteroids, or agents such as corticosteroids, or agents such as lorazepamlorazepam
NCCN Practice Guidelines in Oncology – Version 1. 2007. Antiemesis, MS-1.
Additional TreatmentAdditional Treatment
Options for breakthrough treatment Options for breakthrough treatment were discussed with the patient were discussed with the patient
Dexamethasone + lorazepam were Dexamethasone + lorazepam were added to her antiemetic regimenadded to her antiemetic regimen
Take-Home MessagesTake-Home Messages Many patients receive adjuvant chemotherapy, particularly Many patients receive adjuvant chemotherapy, particularly
those with small node negative breast cancers, for an those with small node negative breast cancers, for an acknowledged small potential benefit (reduction in risk of acknowledged small potential benefit (reduction in risk of recurrence)recurrence)
It is incumbent upon oncologists to deliver adjuvant It is incumbent upon oncologists to deliver adjuvant chemotherapy with as few side effects as possiblechemotherapy with as few side effects as possible
A substantial portion of patients receiving common A substantial portion of patients receiving common regimens such as AC experience CINV despite regimens such as AC experience CINV despite recommended emetic therapyrecommended emetic therapy
There are a variety of options available for the treatment of There are a variety of options available for the treatment of breakthrough CINV, these include dopamine antagonists, breakthrough CINV, these include dopamine antagonists, metoclopramide, butyrophenones, cannabinoids, metoclopramide, butyrophenones, cannabinoids, corticosteroids, or agents such as lorazepamcorticosteroids, or agents such as lorazepam
Case Study: Anticipatory CINVCase Study: Anticipatory CINVand Opioid-Refractory Painand Opioid-Refractory Pain
Judith A. Luce, MDJudith A. Luce, MD
Clinical Professor of Medicine, Clinical Professor of Medicine, University of California, San Francisco University of California, San Francisco
Director, Oncology ServicesDirector, Oncology ServicesSan Francisco General HospitalSan Francisco General Hospital
San Francisco, California San Francisco, California
Ms. FMs. F
Ms. F is a 50-year-old Honduran woman Ms. F is a 50-year-old Honduran woman who was diagnosed with stage II breast who was diagnosed with stage II breast cancer 3 years agocancer 3 years ago
She had been treated with mastectomy, She had been treated with mastectomy, chest wall radiation therapy, 6 cycles of chest wall radiation therapy, 6 cycles of FEC-75 chemotherapy, and tamoxifenFEC-75 chemotherapy, and tamoxifen
She came to our hospital with an enlarging She came to our hospital with an enlarging mass in her sternum and severe painmass in her sternum and severe pain
Ms. FMs. F Incisional biopsy was performed because of a lack Incisional biopsy was performed because of a lack
of information from Honduras—the mass was of information from Honduras—the mass was metastatic triple-negative breast cancermetastatic triple-negative breast cancer
Staging revealed 2 other osseous metastases, right Staging revealed 2 other osseous metastases, right neck nodes, and no visceral diseaseneck nodes, and no visceral disease
Radiation therapy to the sternal mass was delivered, Radiation therapy to the sternal mass was delivered, ultimately helping to reduce painultimately helping to reduce pain
Patient was started on short-acting opioids and Patient was started on short-acting opioids and nonsteroidal anti-inflammatory drug (NSAID) orally, nonsteroidal anti-inflammatory drug (NSAID) orally, but said the NSAID irritated her stomachbut said the NSAID irritated her stomach
Ms. FMs. F
Ms. F returns to clinic having lost 2 kilograms, Ms. F returns to clinic having lost 2 kilograms, complaining of insomnia, anorexia, terrible complaining of insomnia, anorexia, terrible pain, nausea, and fatigue. She is tearful and pain, nausea, and fatigue. She is tearful and depressed. She spends most of her time on the depressed. She spends most of her time on the sofa or in bed sofa or in bed
Opioids are increased, long-acting opioid Opioids are increased, long-acting opioid prescribed, and sertralene and prescribed, and sertralene and prochlorperazine givenprochlorperazine given
Chemotherapy with weekly paclitaxel and Chemotherapy with weekly paclitaxel and bevacizumab is begunbevacizumab is begun
Ms. FMs. F The patient is much worse at her next visit. She The patient is much worse at her next visit. She
has had nearly continuous nausea and vomiting has had nearly continuous nausea and vomiting on weekly chemotherapy, still has poorly on weekly chemotherapy, still has poorly controlled pain, anorexia, and insomnia. She says controlled pain, anorexia, and insomnia. She says she had bad nausea after her original she had bad nausea after her original chemotherapy also. She complains about “all the chemotherapy also. She complains about “all the pills” but does say that the radiation has helped pills” but does say that the radiation has helped her pain a lot. Now another bone hurtsher pain a lot. Now another bone hurts
She is given increased opioids, lorazepam, She is given increased opioids, lorazepam, granisetron, and the chemotherapy is switched to granisetron, and the chemotherapy is switched to every 21 daysevery 21 days
Ms. FMs. F Ms. F continues to have chemotherapy-induced Ms. F continues to have chemotherapy-induced
nausea and vomiting for about a week after nausea and vomiting for about a week after chemotherapy chemotherapy
She now notes that taking the short-acting opioid She now notes that taking the short-acting opioid makes her more nauseated, but she doesn’t feel makes her more nauseated, but she doesn’t feel any immediate relief from the long-acting drug. any immediate relief from the long-acting drug. She notes “no help” from sertralene and She notes “no help” from sertralene and lorazepam, so she stopped them. She has lorazepam, so she stopped them. She has sleepiness from the prochlorperazine sleepiness from the prochlorperazine
Her tumor has progressed Her tumor has progressed
Ms. FMs. F
She remains weepy, discouraged, and She remains weepy, discouraged, and the only medications she takes the only medications she takes regularly are the short- and long-acting regularly are the short- and long-acting opioids, but she takes the PRN only opioids, but she takes the PRN only about twice a day. She has lost 4 more about twice a day. She has lost 4 more kilogramskilograms
Taking chemotherapy “time out,” Taking chemotherapy “time out,” radiation to new bone painradiation to new bone pain
The Perfect StormThe Perfect Storm
This patient hasThis patient has Chemotherapy-induced nausea and vomiting (CINV), Chemotherapy-induced nausea and vomiting (CINV),
with a major contribution from anticipatory NV, since with a major contribution from anticipatory NV, since her regimen is of relatively low emetogenic potentialher regimen is of relatively low emetogenic potential
Anxiety and depressionAnxiety and depression
Anorexia, complicated by selective serotonin reuptake Anorexia, complicated by selective serotonin reuptake inhibitor (SSRI)inhibitor (SSRI)
Nausea from her opioidsNausea from her opioids
Severe bone pain, not well relievedSevere bone pain, not well relieved
Poor compliance due to discouragementPoor compliance due to discouragement
The Perfect StormThe Perfect Storm
Poor quality of life
Opioid analgesics Chemotherapy
Nausea
Pain Anxiety, depression
Fatigue
All of this
Poor compliance
Anorexia
Nausea Issues for This PatientNausea Issues for This Patient
Anticipatory nausea and vomitingAnticipatory nausea and vomiting
Still occurs in about 25% of patients in spite of new Still occurs in about 25% of patients in spite of new antiemeticsantiemetics
Prevention is key: lower incidence when initial CINV Prevention is key: lower incidence when initial CINV is well managedis well managed
Memory? Anxiety? Lorazepam, cannabinoids may Memory? Anxiety? Lorazepam, cannabinoids may reduce incidencereduce incidence
Treat Treat beforebefore chemotherapy chemotherapy
Training measures: visualization, acupressure?Training measures: visualization, acupressure?
1. Dibble SL, et al. Oncol Nurs Forum. 2003;30:E40. 2. Dibble SL, et al. Oncol Nurs Forum. 2004;31:E1. 3. Bloechl-Daum B, et al. J Clin Oncol. 2006;24:4472.
Nausea Issues for This PatientNausea Issues for This Patient
CINV with delayed nauseaCINV with delayed nausea
About half of all patients experience moderate to About half of all patients experience moderate to severe delayed nausea and vomiting even in this era severe delayed nausea and vomiting even in this era of better agentsof better agents
Fewer than half of patients with moderate to severe Fewer than half of patients with moderate to severe CINV after cycle 1 get an adjustment of regimen before CINV after cycle 1 get an adjustment of regimen before cycle 2cycle 211
Association of CINV with fatigue, “down time” is quite Association of CINV with fatigue, “down time” is quite strongstrong22
Nausea causes greater QOL impact than vomitingNausea causes greater QOL impact than vomiting33
1. Gunnarsdottir S, et al. Pain. 2002;99:385. 2. Miaskowski C, et al. J Pain. 2002;3:12. 3. Antoni MH, et al. Am J Psychiatry. 2006;163:1791.
Pain Issues in This PatientPain Issues in This Patient
Fear of opioids, fear of meaning of painFear of opioids, fear of meaning of pain
– Better pain control in patients with lower scores on Pain Barriers Better pain control in patients with lower scores on Pain Barriers scalescale11
– Suggests strong role for patient education, coachingSuggests strong role for patient education, coaching
Compliance with regimenCompliance with regimen
– Cancer patients with an average of 8 hours of pain/day complied Cancer patients with an average of 8 hours of pain/day complied better with long-acting around-the-clock meds, only 25% with better with long-acting around-the-clock meds, only 25% with PRNsPRNs22
– Better pain management is 1 outcome of support interventions Better pain management is 1 outcome of support interventions for stressfor stress33
– Active phone coaching resulted in better pain control by about Active phone coaching resulted in better pain control by about 1/31/344
Pain Management AdjunctsPain Management Adjuncts
Antianxiety drugs, usually benzodiazepinesAntianxiety drugs, usually benzodiazepines
Neuroleptics with neuropathic pain activityNeuroleptics with neuropathic pain activity
Anti-inflammatory agentsAnti-inflammatory agents
Antidepressants: many possibilitiesAntidepressants: many possibilities
CannabinoidsCannabinoids
Topical agents: lidocaine, capsaicinTopical agents: lidocaine, capsaicin
Physical measures: splints, physical therapy, massage, Physical measures: splints, physical therapy, massage, acupuncture, topical physical agentsacupuncture, topical physical agents
Psychosocial measures: active coaching regimen, Psychosocial measures: active coaching regimen, relaxation/meditation, group supportrelaxation/meditation, group support
Cannabinoids and Pain ManagementCannabinoids and Pain Management Use goes back to ancient timesUse goes back to ancient times
Preclinical data for multiple types of pain mechanismsPreclinical data for multiple types of pain mechanisms
Synergy with NSAIDS, acetaminophen, mu opiate receptorsSynergy with NSAIDS, acetaminophen, mu opiate receptors
Clear clinical efficacy in neuropathic pain, including multiple sclerosis and Clear clinical efficacy in neuropathic pain, including multiple sclerosis and rheumatoid arthritis (RA)rheumatoid arthritis (RA)
Modulation of inflammation may also help pain—efficacy in RA, postoperative Modulation of inflammation may also help pain—efficacy in RA, postoperative painpain
Cancer pain studies are fewerCancer pain studies are fewer
– Mostly older studies, small, but randomizedMostly older studies, small, but randomized
– Best was European Sativex study: 43% of patients achieved ≥30% reduction in pain Best was European Sativex study: 43% of patients achieved ≥30% reduction in pain vs placebovs placebo11
– Side effects may be more common with THC vs sativexSide effects may be more common with THC vs sativex
1http://www.dpna.org/1sativex.htm
Lynch M. Pain Res Manage. 2005;10(suppl A).
Cannabinoids and Pain ManagementCannabinoids and Pain Management
Greater potency and efficacy in both inflammatory and neuropathic pain
Comparable in potency and efficacy
Comparison with opioids
Due to up-regulation of CB1 receptorsAllodynia
CB2 receptors play important role
CB2 receptors play important role
Significant evidence
Anti-inflammatory
Due to up-regulation of CB1
receptors_______________Data from animal studies support a
role for CB2 receptors
Significant evidenceSignificant evidence
Hyperalgesia
Significant evidenceSignificant evidenceSignificant evidence
Antinociceptive
NeuropathicChronicVisceralAcute
Type of PainEffects Showed in Preclinical Studies
Cross-Reacting PharmacotherapyCross-Reacting Pharmacotherapy
Nausea medicationsNausea medications
Phenothiazines, butyrophenones: sedation, Phenothiazines, butyrophenones: sedation, potentially desirable CNS effectspotentially desirable CNS effects
Cannabinoids: anxiolytic; synergy with opioids, anti-Cannabinoids: anxiolytic; synergy with opioids, anti-inflammatory agents; orexigenicinflammatory agents; orexigenic
NK1 antagonists, 5HT3 antagonistsNK1 antagonists, 5HT3 antagonists
Benzodiazepines: lorazepam reduces anxiety and Benzodiazepines: lorazepam reduces anxiety and anticipatory nausea/vomiting; improves sleepanticipatory nausea/vomiting; improves sleep
Steroids: orexigenic, anti-inflammatory, moodSteroids: orexigenic, anti-inflammatory, mood
Options for This PatientOptions for This Patient
Better nausea managementBetter nausea management
Continue prochlorperazine, 5HT3Continue prochlorperazine, 5HT3
Addition of cannabinoidAddition of cannabinoid
Regular schedule of administrationRegular schedule of administration
Medi-set and home nursing coachingMedi-set and home nursing coaching
Consider, with new chemotherapy: Consider, with new chemotherapy: aprepitant, steroid taperaprepitant, steroid taper
Options for This PatientOptions for This Patient
Better pain managementBetter pain management
Continue around-the-clock long-acting opioid, increase doseContinue around-the-clock long-acting opioid, increase dose
Emphasize regular use of PRN short-acting opioidEmphasize regular use of PRN short-acting opioid
Add cannabinoidAdd cannabinoid
Trial of NSAID plus proton pump inhibitorTrial of NSAID plus proton pump inhibitor
Home nursing for coaching, physical therapyHome nursing for coaching, physical therapy
Referral to acupuncture and massageReferral to acupuncture and massage
– Change SSRI to either quetiapine or olanzapineChange SSRI to either quetiapine or olanzapine
– Continue PRN lorazepamContinue PRN lorazepam
Case Study: Noncompliance as a Case Study: Noncompliance as a Result of CINV and PainResult of CINV and Pain
Kristen Fessele, RN, MSN, AOCNKristen Fessele, RN, MSN, AOCN
Associate Director, Human Research ServicesAssociate Director, Human Research ServicesThe Cancer Institute of New JerseyThe Cancer Institute of New Jersey
New Brunswick, New JerseyNew Brunswick, New Jersey
Ms. DMs. D
Ms. D is 38 years oldMs. D is 38 years old
Mother of a 6-year-old sonMother of a 6-year-old son
Originally diagnosed with infiltrating ductal Originally diagnosed with infiltrating ductal carcinoma of the right breast at age 33carcinoma of the right breast at age 33
– ER/PR negativeER/PR negative
– Her2/neu amplified by fluorescence in situ Her2/neu amplified by fluorescence in situ hybridization (FISH)hybridization (FISH)
Ms. DMs. D
Received doxorubicin + cyclophosphamide Received doxorubicin + cyclophosphamide followed by paclitaxel (trastuzumab was not followed by paclitaxel (trastuzumab was not given adjuvantly outside clinical trials at that given adjuvantly outside clinical trials at that time)time)
Had difficulties with postchemotherapy nausea Had difficulties with postchemotherapy nausea and vomiting, as well as anticipatory vomitingand vomiting, as well as anticipatory vomiting
Developed herpes zoster to the left upper Developed herpes zoster to the left upper chest (C3 dermatome) in cycle 6; continues to chest (C3 dermatome) in cycle 6; continues to experience poorly controlled postherpetic experience poorly controlled postherpetic neuralgianeuralgia
Ms. DMs. D
Relapsed with a solitary pulmonary Relapsed with a solitary pulmonary metastasis 7 months agometastasis 7 months ago
– Receives paclitaxel, cisplatin and Receives paclitaxel, cisplatin and trastuzumab with a 75% decrease in size trastuzumab with a 75% decrease in size of lesionof lesion
Has recently “forgotten” several lab Has recently “forgotten” several lab appointments, and this week did not appointments, and this week did not appear for her treatment appointmentappear for her treatment appointment
““I can’t take this anymore, and nothing I can’t take this anymore, and nothing you’ve given me is really helping!”you’ve given me is really helping!”
Complaining of:Complaining of:
Poorly controlled nausea after chemotherapy Poorly controlled nausea after chemotherapy despite use of 5-day antiemetic regimen despite use of 5-day antiemetic regimen posttreatment includingposttreatment including
– DexamethasoneDexamethasone
– OndansetronOndansetron
– ProchlorperazineProchlorperazine
Increasing frequency and intensity of postherpetic Increasing frequency and intensity of postherpetic neuralgia neuralgia
““I dread chemo all week because I I dread chemo all week because I know I’m going to feel even worse know I’m going to feel even worse
afterwards…”afterwards…”
Patient’s fear of nausea and vomiting is Patient’s fear of nausea and vomiting is causing her to become noncompliant causing her to become noncompliant with her chemotherapy planwith her chemotherapy plan
– May jeopardize the stability of her disease May jeopardize the stability of her disease responseresponse
Overall symptom burden is draining her Overall symptom burden is draining her coping reservecoping reserve
““I hate this –if I take all those pills, I’m I hate this –if I take all those pills, I’m too sleepy to do anything, and if I don’t, too sleepy to do anything, and if I don’t,
I can’t sleep, and I’m tired anyway…”I can’t sleep, and I’m tired anyway…” Ms. D has not acclimated to opiate-induced Ms. D has not acclimated to opiate-induced
sedation as most patients do, possibly due to sedation as most patients do, possibly due to her inconsistent dosing patternher inconsistent dosing pattern
Gabapentin, used specifically for her Gabapentin, used specifically for her neuropathic pain (as well as for hot flashes neuropathic pain (as well as for hot flashes due to chemotherapy-induced premature due to chemotherapy-induced premature menopause), also induces unacceptable menopause), also induces unacceptable sedation in this patientsedation in this patient
Topical lidocaine application provides some, Topical lidocaine application provides some, but incomplete, relief of postherpetic neuralgiabut incomplete, relief of postherpetic neuralgia
Pain ManagementPain Management
Ms. D has used oxycodone 5 mg with Ms. D has used oxycodone 5 mg with acetaminophen 325 mg, 1–2 tablets once acetaminophen 325 mg, 1–2 tablets once or twice daily to make her postherpetic or twice daily to make her postherpetic neuralgia pain “almost bearable”neuralgia pain “almost bearable”
Lidocaine patches offer some reliefLidocaine patches offer some relief
She has also tried gabapentin at varying She has also tried gabapentin at varying (but suboptimal) doses and schedules (but suboptimal) doses and schedules without good effect, as she finds it too without good effect, as she finds it too sedating to fully escalatesedating to fully escalate
1. Cepeda MS, et al. Clin Pharmacol Ther. 2003;74:102. 2. Swegle JM, Logemann C. Am Fam Physician. 2006;74:1347. 3. Cherny N, et al. J Clin Oncol. 2001;19:2542. 4. McNicol E, et al. J Pain. 2003;4:231.
Common Opioid-Induced Adverse EffectsCommon Opioid-Induced Adverse Effects Nausea/vomitingNausea/vomiting
– Approximately 25% of patientsApproximately 25% of patients11
– Usually transientUsually transient22
SedationSedation– Between 20% and 60% of patientsBetween 20% and 60% of patients33
– Usually at initiation of therapy or with dose increasesUsually at initiation of therapy or with dose increases44
ConstipationConstipation– Most common side effectMost common side effect22
PruritisPruritis– Between 2% and 10% of patientsBetween 2% and 10% of patients33
1. Cepeda MS, et al. Clin Pharmacol Ther. 2003;74:102. 2. Forman WB. Clin Geriatr Med.1996;12:489.
Opioid-Induced Adverse EffectsOpioid-Induced Adverse Effects Risk Factors Risk Factors
GenderGender
– Nausea/vomiting are more likely to occur in Nausea/vomiting are more likely to occur in women than in menwomen than in men11
RaceRace
– Nausea/vomiting are more likely to occur in Nausea/vomiting are more likely to occur in Caucasian-Americans than in African-AmericansCaucasian-Americans than in African-Americans11
AgeAge
– Age-related reduction in renal function may lead to Age-related reduction in renal function may lead to accumulation of opioids and their metabolitesaccumulation of opioids and their metabolites1,21,2
Cherny N, et al. J Clin Oncol. 2001;19:2542.
Approaches for ManagingApproaches for ManagingOpioid-Induced Adverse EffectsOpioid-Induced Adverse Effects
Dose reduction of opioidDose reduction of opioid
Symptomatic management of adverse Symptomatic management of adverse effecteffect
Opioid rotationOpioid rotation
Switching route of systemic Switching route of systemic administrationadministration
GoalsGoals
More effective, reliable control of More effective, reliable control of nausea and vomitingnausea and vomiting
More effective control of neuropathic More effective control of neuropathic painpain
Increased compliance with treatment Increased compliance with treatment plan to allow continued response to plan to allow continued response to chemotherapy regimenchemotherapy regimen
Tumor Board PresentationTumor Board Presentation
During discussion of challenging During discussion of challenging management cases at weekly tumor management cases at weekly tumor board, Ms. D was reviewedboard, Ms. D was reviewed
A colleague, trained in Canada, A colleague, trained in Canada, suggested a trial of a cannabinoid suggested a trial of a cannabinoid adjuvant to improve the symptom adjuvant to improve the symptom clustercluster
1. Cichewicz DL. Life Sci. 2004;74:1317. 2. Manzanares J, et al. Trends Pharmacol Sci. 1999;20:287. 3. Reche I, et al. Eur J Pharmacol. 1996;318:11. 4. Campbell F. BMJ. 2001;323:13.
Compelling Preclinical Data—More Compelling Preclinical Data—More Evidence Is NeededEvidence Is Needed
Several studies describe the Several studies describe the potentiating effects of opioids and potentiating effects of opioids and cannabinoids on paincannabinoids on pain1-31-3
Systematic review of human studies in Systematic review of human studies in BMJBMJ 2001 by Campbell et al noted 2001 by Campbell et al noted
– “…“…suggestions of efficacy in spasticity suggestions of efficacy in spasticity and neuropathic pain”and neuropathic pain”44
GW Pharmaceuticals, 1/4/06 (Press release)
Clinical Trials Under WayClinical Trials Under WaySativexSativex
A biologically derived compound of A biologically derived compound of tetrahydrocannabinol (THC) and cannbidiol tetrahydrocannabinol (THC) and cannbidiol (CBD), administered as an oromucosal spray, (CBD), administered as an oromucosal spray, is used in the United Kingdom for is used in the United Kingdom for neuropathic pain and spasticity associated neuropathic pain and spasticity associated with multiple sclerosiswith multiple sclerosis
– FDA approved IND status for Cannabis sativa L. FDA approved IND status for Cannabis sativa L. extract in 2006, allowing start of phase III trial in extract in 2006, allowing start of phase III trial in the United States to evaluate effect of this the United States to evaluate effect of this compound on patients with cancer experiencing compound on patients with cancer experiencing chronic painchronic pain
Available at: http://clinicaltrials.gov/ct/action/GetStudy. Accessed May 16, 2007.
Clinical Trials Under WayClinical Trials Under WayNabiloneNabilone
Phase IV multicenter trial of nabilone in Phase IV multicenter trial of nabilone in patients with diabetic peripheral neuropathypatients with diabetic peripheral neuropathy
– Average, worst pain; pain at night scoresAverage, worst pain; pain at night scores
– Other QOL measuresOther QOL measures
Phase IV multicenter trial of nabilone in Phase IV multicenter trial of nabilone in patients receiving initial chemotherapypatients receiving initial chemotherapy
– Cycle 1: standard antiemetic regimenCycle 1: standard antiemetic regimen
– Cycle 2: standard regimen plus nabiloneCycle 2: standard regimen plus nabilone
1. CesametTM (nabilone) Product Information. Costa Mesa, CA: Valeant Pharmaceuticals; 2006. 2. Marinol® (dronabinol) Product Information. Marietta, GA: Unimed Pharmaceuticals; 2006.
Cannabinoid IndicationsCannabinoid Indications
Nabilone and dronabinolNabilone and dronabinol1,21,2
– Nausea and vomiting that has not Nausea and vomiting that has not responded adequately to conventional responded adequately to conventional antiemetic treatments antiemetic treatments
DronabinolDronabinol22
– Appetite loss associated with weight loss Appetite loss associated with weight loss in people with AIDSin people with AIDS
RecommendationsRecommendations
Educate patient onEducate patient on
– Product natureProduct nature
– Potential benefitsPotential benefits
– Side effectsSide effects
– Risk of addictionRisk of addiction
Develop a treatment plan incorporating these goalsDevelop a treatment plan incorporating these goals
– Reduction in painReduction in pain
– Increased functional abilitiesIncreased functional abilities
– Improved sleep qualityImproved sleep quality
– Increased quality of lifeIncreased quality of life
– Reduction in the use of other medicationsReduction in the use of other medications
1. CesametTM (nabilone) Product Information. Costa Mesa, CA: Valeant Pharmaceuticals; 2006. 2. Marinol® (dronabinol) Product Information. Marietta, GA: Unimed Pharmaceuticals; 2006.
Precautions—Nabilone and DronabinolPrecautions—Nabilone and Dronabinol
Use with caution in Use with caution in
– Older patientsOlder patients1,21,2
– Those with current or previous psychiatric Those with current or previous psychiatric disorders (bipolar disorder, depression, disorders (bipolar disorder, depression, schizophrenia)schizophrenia)1,21,2
– Those with cardiac conditions or at risk Those with cardiac conditions or at risk for tachycardia or orthostatic for tachycardia or orthostatic hypotensionhypotension1,21,2
– Those with a history of seizuresThose with a history of seizures22
Most Common Adverse EventsMost Common Adverse Events
NabiloneNabilone11
– DrowsinessDrowsiness
– VertigoVertigo
– Dry mouthDry mouth
– Euphoria (“feeling high”)Euphoria (“feeling high”)
– AtaxiaAtaxia
– HeadacheHeadache
– Concentration Concentration difficultiesdifficulties
DronabinolDronabinol22
– Euphoria (“high”) Euphoria (“high”)
– Abdominal painAbdominal pain
– Nausea/vomitingNausea/vomiting
– DizzinessDizziness
– SomnolenceSomnolence
– Paranoid reactionParanoid reaction
– Abnormal thinkingAbnormal thinking
1. CesametTM (nabilone) Product Information. Costa Mesa, CA: Valeant Pharmaceuticals; 2006. 2. Marinol® (dronabinol) Product Information. Marietta, GA: Unimed Pharmaceuticals; 2006.
Patient Update/SummaryPatient Update/Summary
Nabilone was added to Ms. D’s antiemetic Nabilone was added to Ms. D’s antiemetic regimen on her most recent cycle. She regimen on her most recent cycle. She reports good improvement in her nausea reports good improvement in her nausea control, and no episodes of vomiting. She is control, and no episodes of vomiting. She is continuing use of a pain diary to track dosing continuing use of a pain diary to track dosing of breakthrough opioids, and reports an of breakthrough opioids, and reports an overall improvement in symptom burden.overall improvement in symptom burden.
ConclusionsConclusions Additional options for symptom management Additional options for symptom management
are beneficial, especially for patients with are beneficial, especially for patients with metastatic disease and multiple sources of metastatic disease and multiple sources of distressdistress
Cannabinoids may prove to be a helpful Cannabinoids may prove to be a helpful adjunct to standard antiemetic regimens and adjunct to standard antiemetic regimens and to opioids for pain managementto opioids for pain management
– Clinical studies are under way to evaluate if Clinical studies are under way to evaluate if cannabinoids may help to reduce the dose of cannabinoids may help to reduce the dose of opioids neededopioids needed
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