Perspectives on Recent Clinical Practice Guideline Updates for the Management of Chemotherapy-Induced Nausea and Vomiting

1
Perspectives on Recent Clinical Practice
Guideline Updates for the Management of
Chemotherapy-Induced Nausea and Vomiting
Faculty Steven M. Grunberg, MD Kimberly Noonan,
MS, RN, ANP, AOCN James J. Natale, PharmD,
BCOP Atheer A. Kaddis, PharmD
2
Updates to Guidelines for Chemotherapy-Induced
Nausea and Vomiting (CINV)

• Despite advances in antiemetic therapies and
  evidence-based practice guidelines, there is a
  marked need for improvement in preventing CINV
• The occurrence of CINV should not be perceived by
  patients as an unavoidable consequence of
  chemotherapy
• Optimal control demands a multidisciplinary
  approach tailored to the individual patient
• Involves the oncologist, hematologist, oncology
  nurse, and oncology pharmacist
• Requires diligent, ongoing monitoring of
  chemotherapy-induced side effects
• The oncology team must be equipped with the tools
  to
• Improve outcomes
• Minimize complications
• Reduce the burden and cost of inadequately
  controlled CINV

3
CINV

• A common and problematic side effect of
  chemotherapy
• Can be prevented in nearly 70 of patients
  receiving HEC1
• 5 Classifications2

CINV Classification Description
Acute Occurs minutes to hours after chemotherapy
Delayed Develops 24 hours after chemotherapy
Anticipatory Typically occurs before chemotherapy after a negative past experience
Breakthrough Occurs despite antiemetic treatment requires rescue
Refractory Occurs during subsequent treatment cycles
HEC highly emetogenic chemotherapy. 1.
Herrstedt J. Nat Clin Pract Oncol.
2008532-43. 2. National Comprehensive Cancer
Network. NCCN Clinical Practice Guidelines in
Oncology. Antiemesis, V.1.2012. July 20, 2011.
4
Overall Impact of CINV

• Consequences of inadequately controlled CINV
• Affects a patients quality of life disrupts
  physical, emotional, cognitive, and functional
  well-being1
• A hurdle to treatment compliance
• Potentially serious and costly physiologic
  complications2
• Delay or discontinuation from potentially
  beneficial or curative anticancer therapy
• Increased healthcare resources and costs
• For patients with uncontrolled CINV versus those
  with controlled CINV3
• Direct medical costs per patient per month were
  1300 higher
• Indirect costs were 433 higher
• Work days lost per month increased by 3 days

1. Vanscoy GJ, et al. Community Oncol.
20052(2)127-132. 2. National Comprehensive
Cancer Network. NCCN Clinical Practice
Guidelines in Oncology. Antiemesis, V.1.2012.
July 20, 2011. 3. Tina Shih YC, et al. Cancer.
2007110678-685.
5
Preventing and/or Managing CINV

• Antiemesis Treatment Goals
• Preventing CINV is the overall goal1
• Other goals
• Avoiding drug-drug interactions and other adverse
  effects2
• Providing protection throughout the full
  anticipated period of risk1
• At least 3 days after the last dose of HEC
• For 2 days after the last dose of MEC
• Treatment Considerations3
• Classification of CINV
• Emetogenicity of chemotherapy
• Based on the chemotherapy agent/regimens emetic
  risk (See Emetic Risk Designation Antineoplastic
  Agents, Slide 10)

MEC moderately emetogenic chemotherapy. 1.
National Comprehensive Cancer Network. NCCN
Clinical Practice Guidelines in Oncology.
Antiemesis, V.1.2012. July 20, 2011. 2. Georgy A,
et al. Am J Health Syst Pharm. 200764(21)2227-22
36. 3. Tipton JM, et al. Clin J Oncol Nurs.
200711(1)69-78.
6
Pharmacologic Treatments for CINV
Drug Class Agents FDA-Approved Indication Formulations
5-HT3 RAs 1st generation Dolasetron1 Prevention of CINV associated with MEC, including initial and repeat courses aA safety alert was issued by the FDA stating the injection formulation of dolasetron was not safe for CINV, based on data showing it was associated with abnormal heart rhythms (QT, PR, QRS prolongation).2 Oral (Per FDA, injection no longer recommended)a
Granisetron3 Prevention of nausea and/or vomiting associated with initial and repeat courses of emetogenic cancer treatment, including high-dose cisplatin Granisetron transdermal system4 prevention of CINV in patients receiving MEC and/or HEC for up to 5 consecutive days Oral solution, IV injection, transdermal system
Ondansetron5 Prevention of CINV associated with HEC, including cisplatin 50 mg/m2 prevention of CINV associated with initial and repeat courses of MEC bIn September 2011, the FDA issued a drug safety communication advising that abnormal heart rhythms (QT prolongation) may be associated with ondansetron.6 This agent should be avoided in patients with congenital long QT syndrome ECG monitoring is recommended for patients with electrolyte abnormalities, congestive heart failure, bradyarrhythmias, or those taking medications that prolong the QT interval.6 Tablets, orally disintegrating tablet, oral solution, injectionb
2nd generation Palonosetron7 Prevention of both acute and delayed CINV associated with initial and repeat courses of MEC prevention of acute CINV associated with initial and repeat courses of MEC Injection (oral not currently available in the US)8
RAs receptor antagonists. 1. Anzemet
(dolasetron mesylate) package insert 2011. 2.
Anzemet (dolasetron mesylate) Drug safety
communication. December 17, 2010. 3. Kytril
(granisetron hydrochloride) Injection, for
intravenous use package insert 2011. 4.
Sancuso (granisetron transdermal system) package
insert 2008. 5. Zofran (ondansetron
hydrochloride) tablets, Zofran ODT, and Zofran
oral solution 2011. 6. FDA Drug Safety
Communication Zofran (ondansetron). September
15, 2011. 7. Aloxi (palonosetron HCl) injection
for intravenous use package insert 2009. 8.
National Comprehensive Cancer Network. NCCN
Clinical Practice Guidelines in Oncology.
Antiemesis, V.1.2012. July 20, 2011.
7
Pharmacologic Antiemetic Treatments (Contd)
Drug Class Agents FDA-Approved Indication Formulations
NK1 RAs Aprepitant1 In combination with other antiemetic agents for the prevention of acute and delayed CINV associated with initial and repeat courses of HEC, including high-dose cisplatin and for the prevention of CINV associated with initial and repeat courses of MEC Oral
Fosaprepitant2 (an IV prodrug of aprepitant) In combination with other antiemetic agents for the prevention of CINV associated with initial and repeat courses of HEC, including high-dose cisplatin and for the prevention of CINV with initial and repeat courses of MEC IV injection
NK neurokinin IV intravenous. 1. Emend
(aprepitant) capsules package insert 2011. 2.
Emend (fosaprepitant) for injection package
insert 2011.
8
Other Pharmacologic Antiemetic Treatments

• Benzodiazepines
• Lorazepam (oral tablet or liquid)
• Steroids
• Dexamethasone (oral tablet and injection)
• Cannabinoids
• Dronabinol (oral tablet)
• Nabilone (oral tablet)

9
Emetic Risk Designation Antineoplastic Agents
Emetic Risk Single Antineoplastic Agents Administered Intravenously1 Emetic Risk Single Antineoplastic Agents Administered Intravenously1 Emetic Risk Single Antineoplastic Agents Administered Intravenously1 Emetic Risk Single Antineoplastic Agents Administered Intravenously1 Emetic Risk Single Antineoplastic Agents Administered Intravenously1
High Moderate Low Low Minimal
Carmustine Cisplatin Cyclophosphamide gt1500 mg/m2 Dacarbazine Dactinomycin Mechlorethamine Streptozotocin Azacitidine Alemtuzumab Bendamustine Carboplatin Clofarabine Cyclophosphamide lt1500 mg/m2 Cytarabine gt1000 mg/m2 Daunorubicina Doxorubicina Epirubicina Idarubicina Ifosfamide Irinotecan Oxaliplatin Fluorouracil Bortezomib Cabazitaxel Catumaxomab Cytarabine lt1000 mg/m2 Docetaxel Doxorubicin HCl liposome injection Etoposide Gemcitabine Ixabepilone Methotrexate Mitomycin Mitoxantrone Paclitaxel Panitumumab Pemetrexed Temsirolimus Topotecan Trastuzumab 2-Chlorodeoxyadenosine Bevacizumab Bleomycin Busulfan Cetuximab Fludarabine Pralatrexate Rituximab Vinblastine Vincristine Vinorelbine
aThese anthracyclines, when combined with
cyclophosphamide, are now designated as high
emetic risk. This is not a complete list of
agents. 1. Adapted with permission from Basch E,
et al. J Clin Oncol. 201129(30)4189-4198.
ASSUMES PERMISSION WAS REQUESTED/GRANTED
10
Clinical Practice Guidelines CINV

• Clinical practice guidelines
• A framework to help practitioners prevent and/or
  manage CINV in the individual with cancer
• Guidelines for antiemesis are released by these
  key societies
• American Society of Clinical Oncology (ASCO)
  (updated in 2011)1
• National Comprehensive Cancer Network (NCCN)
  (updated in July 2011)2
• Multinational Association of Supportive Care in
  Cancer (MASCC) in conjunction with European
  Society of Medical Oncology (ESMO) (updated in
  2011)3
• Oncology Nursing Society (ONS) Putting Evidence
  Into Practice (PEP) recommendations were released
  in 20074

1. Basch E, et al. J Clin Oncol.
201129(31)4189-4198. 2. National Comprehensive
Cancer Network. NCCN Clinical Practice
Guidelines in Oncology. Antiemesis, V.1.2012.
July 20, 2011. 3. Gralla RJ, et al. MASCC/ESMO
Antiemetic Guideline 2011. 4. Tipton JM, et al.
Clin J Oncol Nurs. 200711(1)69-78.
11
ASCO Antiemetic Guidelines Update 2011

• Key changes in the 2011 update1
• Combined anthracycline cyclophosphamide (AC)
  regimens were reclassified as highly emetic
• For patients receiving HEC, the recommended
  antiemetic therapy is a 3-drug combination 5-HT3
  RA NK1 RA dexamethasone
• The equivalency of fosaprepitant was validated,
  based on a large clinical trial
• For MEC regimens, preferential use of
  palonosetron is recommended, combined with
  dexamethasone
• For low emetic-risk agents, dexamethasone can be
  used before the first chemotherapy dose
• For combined chemotherapy regimens, antiemesis
  should be based on the chemotherapy agent with
  the greatest degree of emetic risk

1. Basch E, et al. J Clin Oncol.
201194189-4198.
12
NCCN Updated Antiemetic Guidelines

• Changes reflected in the July 2011 update1
• For acute and delayed emesis prevention with HEC,
  preferred was added to palonosetron 0.25 mg IV
  day 1
• For emesis prevention in MEC, preferred was added
  to palonosetron 0.25 mg IV day 1, with a footnote
  stating, Data with palonosetron is based on
  randomized studies with 2 drug combinations.
• For emesis prevention in MEC, a Category 1
  designation (high level of evidence with uniform
  consensus) was added to granisetron 2 mg PO or 1
  mg PO BID or 0.01 mg/kg (max 1 mg) IV day 1
• Several changes to the emetogenic potential of IV
  antineoplastic agents
• Eribulin was assigned a low emetic risk
• Ipilimumab and ofatumumab were assigned a minimal
  emetic risk
• Vandetanib was assigned a minimal to low risk
• Similar to the ASCO guidelines, NCCN guidelines
  recommend, Antiemetic regimens should be chosen
  based on the drug with the highest emetic risk as
  well as patient-specific factors.1

PO by mouth BID twice daily. 1. National
Comprehensive Cancer Network. NCCN Clinical
Practice Guidelines in Oncology. Antiemesis,
V.1.2012. July 20, 2011.
13
Obstacles to Optimal Antiemetic Care

• Steven M. Grunberg, MD
• Professor of Medicine
• The University of Vermont College of Medicine
• Burlington, VT

14
Challenges in Delivering Optimal Antiemetic Care

• Clinical Practice Guidelines for Antiemesis
• Interpreting the guidelines may present
  challenges
• Although there are more similarities than
  differences among guidelines, differences exist
• These differences can influence recommendations
  by a specific group
• Gaps exist in the guidelines
• Accuracy is a worthy goal however
• Evidence is generally from large, randomized,
  placebo-controlled trials
• Guidelines cannot possibly represent all clinical
  scenarios
• Being comprehensive is also a key goal however
• In some cases, the best available evidence may
  consist of expert opinions
• Some recommendations may be controversial
• Guidelines are not proclamations, but rather a
  starting point for clinical judgment and further
  research

15
Obstacles to Optimal Antiemetic Care

• Failure to recognize the extent of the problem
• Delayed vomiting (2-5 days after treatment) often
  occurs at home after the patient is out of view
  of the clinical staff
• Studies have shown that clinicians seriously
  underestimate the incidence of delayed CINV1-3
• It is imperative for clinicians to be aware of
  clinical settings in which delayed vomiting is
  likely to occur
• Palonosetron, a 2nd-generation serotonin RA, has
  shown better clinical activity against delayed
  vomiting4
• Aprepitant, an NK1 RA, preferentially acts
  against delayed nausea and vomiting5

1. Grunberg SM, et al. Cancer. 2004100(10)2261-2
268. 2. Erazo Valle A, et al. Curr Med Res Opin.
200622(12)2403-2410. 3. Liau CT, et al. Support
Care Cancer. 200413277-286. 4. Eisenberg P, et
al. Cancer. 200398(11)2473-2482. 5. Hesketh PJ,
et al. J Clin Oncol. 200321(22)4112-4119.
16
Obstacles to Optimal Antiemetic Care (Contd)

• Differentiating between nausea and vomiting
• Although nausea and vomiting are correlated, each
  represents a separate entity1
• Vomiting is an objective, quantifiable action
• Nausea is a subjective, qualitative feeling
• Different neural pathways may be involved
• Several agents may be required for optimal
  prevention
• Some agents are more effective at preventing
  vomiting others are more effective at preventing
  nausea
• Use of complementary agents may lead to better
  control
• Therapies have different mechanisms of action
• These differences may provide insights for even
  more selective and effective drugs for nausea and
  vomiting

1. Molassiotis J, et al. Eur J Cancer Care.
200817(5)444-453.
17
Effective Prevention and Management of CINV

• Kimberly Noonan, MS, RN, ANP, AOCN
• Chief Nurse Practitioner
• Dana-Farber Cancer Institute
• Boston, MA

18
Effective CINV Prevention and Management

• Oncology nurses can help improve patient outcomes
  by anticipating and effectively managing symptoms
• Role of oncology nurses
• Carefully assessing risk factors
• Communicating and interacting with patients and
  caregivers
• Updating knowledge of the latest agents and
  evidence-based clinical practice guidelines
• Addressing commonly occurring challenges,
  including delayed and breakthrough CINV
• Preventing and managing CINV and preserving
  quality of life for patients with cancer
  receiving chemotherapy

19
Effective CINV Prevention and Management (Contd)

• Identifying key risk factors for CINV
• Greatest risk emetogenic potential of the
  chemotherapeutic agent or regimen
• Review agents and dosages to determine level of
  risk (high, moderate, low, or minimal)
• Increased risk with higher doses, multiday
  regimens, and faster infusion times1
• Patient-specific factors
• Gender, age, history of alcohol consumption,
  previous episodes of nausea and vomiting

1. Lohr L. Cancer J. 200814(2)85-93.
20
Effective CINV Prevention and Management (Contd)

• Consequences of uncontrolled CINV
• Can lead to potentially serious complications and
  an even greater deterioration in quality of life
• May impact a patients decision to continue with
  an effective course of therapy
• Patients with uncontrolled acute CINV are more
  likely to report episodes of delayed CINV1
• Preventing CINV during initial chemotherapy
  cycles is crucial, given that poor emetic control
  at treatment onset predisposes patients to
  problems later on

1. Hesketh PJ, et al. Support Care Cancer.
201018(9)171-177. Abstract.
21
Effective CINV Prevention and Management (Contd)

• Clinical practice guidelines are valuable
  resources for the oncology team
• ASCO, NCCN, MASCC, and ONS Putting Evidence into
  Practice
• Nurses must be familiar with guideline updates as
  a rationale for using recommended therapies
• Cost issues may prevent some patients from
  receiving the most effective care
• It is important to address financial issues
  (formulary restrictions, out-of-pocket expenses)
  prior to initial therapy
• Breakthrough nausea and vomiting
• Remains a significant challenge
• Difficult to reverse, reinforcing the need for
  optimal prevention strategies
• May require around-the-clock dosing versus
  as-needed dosing

22
Optimizing Antiemetic Therapy Progress and
Ongoing Challenges

• James J. Natale, PharmD, BCOP
• Clinical Pharmacy Specialist
• UPMC Cancer Centers
• Pittsburgh, PA

23
Optimizing Antiemetic Therapy

• Serotonin (5-HT3) RAs
• Cornerstone antiemetic therapy for MEC and HEC1-4
• 1st-generation agents dolasetron, granisetron,
  and ondansetron
• 2nd-generation agent palonosetron
• Palonosetron is the only 5-HT3 RA approved by the
  FDA for MEC and prevention of acute CINV for HEC5
• Majority of updated guidelines list palonosetron
  as the preferred 5-HT3 RA when used in either
  2- or 3-drug combinations (with dexamethasone
  and/or an NK1 RA, respectively) for the
  prevention of acute and delayed CINV prior to MEC
  and HEC, particularly MEC1-3

1. National Comprehensive Cancer Network. NCCN
Clinical Practice Guidelines in Oncology.
Antiemesis, V.1.2012. July 20, 2011. 2. Basch E,
et al. J Clin Oncol. 201129(31)4189-4198. 3.
Gralla RJ, et al. MASCC/ESMO Antiemetic
Guidelines. 2011. 4. Tipton JM, et al. Clin J
Oncol Nurs. 200711(1)69-78. 5. Aloxi
(palonosetron HCl) package insert 2009.
24
The Role of Antiemetic Guidelines in Promoting
Value-Based Care

• Atheer A. Kaddis, PharmD
• Senior Vice President
• Managed Markets/Clinical Services
• Diplomat Specialty Pharmacy
• Flint, MI

25
Role of Antiemetic Guidelines in Promoting
Value-Based Care

• Costs associated with uncontrolled CINV can be
  significant
• Direct and indirect costs may include1
• Acquisition of specific antiemetic drugs
• Costs associated with unscheduled office or
  emergency department visits, hospital admissions,
  loss of productivity
• Clinical practice guidelines
• Promote effective use of antiemetic agents, which
  can lead to improved patient outcomes at a lower
  cost to the institution

1. Haiderali A, et al. Support Care Cancer.
201119(6)843-851.
26
Role of Antiemetic Guidelines in Promoting
Value-Based Care (Contd)

• Factors that can complicate CINV prevention and
  management
• Lack of awareness of guidelines/updates
• All members of the healthcare team should be
  familiar with updates
• Once awareness is achieved
• Considerations involve differences in cost
  between previously accepted therapies and novel
  recommended agents
• Should IV or oral therapies be used, especially
  when choosing 5-HT3 RAs?
• Although IV palonosetron is the preferred 5-HT3
  RA for prevention in HEC, can acute and delayed
  CINV be effectively treated with a 1st-generation
  5-HT3 RA?
• Should we look beyond the direct cost of a
  particular agent and consider how more effective
  control of symptoms may reduce the need for
  supplemental and rescue antiemetics, resulting in
  fewer office visits or hospitalizations for
  delayed or breakthrough CINV?
• When choosing between 5-HT3 RAs, other than
  palonosetron, should oral formulations be given
  preference over IV formulations based on cost?

27
Role of Antiemetic Guidelines in Promoting
Value-Based Care (Contd)

• Other unresolved issues relevant to the optimal
  duration of therapy
• CINV prevention should last over a 3-day period,
  beginning 1 day before administration, with
  therapies recommended in the NCCN and ASCO
  guidelines1,2
• The management of breakthrough CINV occurs over a
  longer period of time and is highly dependent on
• the emetogenic potential of a particular regimen,
• the number of cycles of therapy, and
• patient-related risk factors

1. National Comprehensive Cancer Network. NCCN
Clinical Practice Guidelines in Oncology.
Antiemesis, Version 1.2012. July 20, 2011. 2.
Basch E, et al. J Clin Oncol. 201129(31)4189-419
8.
28
Optimizing Antiemetic Therapy (Contd)

• Despite the availability of effective therapies
  and updated guidelines, challenges in managing
  CINV persist
• Current guidelines are based primarily on data
  from single-day chemotherapy regimens
• More prospective data are needed to determine
  optimal utilization of newer drug classes for
  multiday regimens
• Guidelines may need to be tempered when assessing
  an individuals risk for CINV, so necessary
  adjustments to preferred prophylactic antiemetic
  regimen can be made
• Considerations may include
• Variability in renal and liver function
• Other comorbidities
• Financial and insurance issues
• Experiences with previous chemotherapy cycles

29
Optimizing Antiemetic Therapy (Contd)

• In most studies, emesis control appears to be
  better than nausea control, especially in the
  delayed setting
• There is a need for more prospective data to
  clearly quality and quantify the impact of
  uncontrolled CINV and its effect on patient
  outcomes
• Essential action steps include
• Adherence to guidelines and
• Focus on complete prevention of CINV in all
  cycles of chemotherapy essential

30
Conclusions/Key Takeaways

• Inadequately controlled CINV can lead to
  potentially serious and costly consequences,
  particularly for patients with delayed CINV
• Despite advances, improvement in controlling CINV
  is needed
• Strategies for improvement include
• Collaborating with all members of the oncology
  team
• Using available resources and tools for patient
  communication and monitoring
• Selecting the appropriate therapy, based on
  patient-specific needs
• Integrating the latest evidence-based guidelines
  and tools into everyday practice
• Has the potential to improve outcomes and reduce
  costs