Disclaimer

This slide deck in its original and unaltered format is for educational purposes and is current as of July 2014. All materials contained herein reflect the views of the faculty, and not those of Educational Concepts Group, LLC or the commercial supporter(s).

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for specific patient management.

Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

Disclaimer

This slide deck is provided for educational purposes and individual slides may be used for personal, non-commercial presentations only if the content and references remain unchanged.

No part of this slide deck may be published or distributed in print or electronic format without prior written permission from Educational Concepts Group, LLC. Additional terms and conditions may apply.

Usage Rights

FACULTY

Egidio Del Fabbro, MD – CHAIRAssociate Professor Director, Palliative Care Program Division of Hematology, Oncology and Palliative Care Virginia Commonwealth University Richmond, Virginia

Jeffrey Crawford, MDGeorge Barth Geller Professor for Research in CancerCo-Director, Solid Tumor Therapeutics ProgramDuke Cancer InstituteDurham, North Carolina Dorothy MK Keefe, PSM, MDService Director, SA Cancer Service Professor of Cancer Medicine, University of Adelaide Adelaide, Australia David Warr, MD, FRCPCAssociate Professor, Department of MedicineUniversity of TorontoHead, Breast Medical OncologyPrincess Margaret Cancer Centre Toronto, Canada

Managing the Conundrum of Anorexia-Cachexia in Advanced NSCLC

Jeffrey Crawford, MDDuke Cancer Institute

• 1. co•nun•drum– kəˈnəndrəm/– noun

• noun: conundrum; plural noun: conundrums• 1. a confusing and difficult problem or question.• "one of the most difficult conundrums for the

experts"– synonyms: problem, difficult question, difficulty,

quandary, dilemma

Google.com

International Consensus Definition of “Cancer Cachexia”

“Multifactorial syndrome defined by an ongoing loss of skeletal muscle mass (with or without fat mass) that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment.”

Fearon K, et al. Lancet Oncol. 2011 May;12(5):489-95.

Freq

uenc

y

6 month weight loss history (%)

Distribution of Pre-Diagnosis Weight Loss in Patients Presenting with NSCLC IIIB / IV

Among a Population Cohort in Northern Alberta

15% weight stable

Baracos VE, et al. Am J Clin Nutr. 2010;91(4):1133S-1137S.

Mean weight loss at presentation

6%

Body mass index (kg/m2)

Freq

uenc

y

BMI Distribution of Patients Presenting with NSCLC IIIB / IV

Population Cohort Northern Alberta, n=950

Gallagher D and DeLegge M. JPEN J Parenter Enteral Nutr. 2011 Sep;35(5 Suppl):21S-8S.

BMI < 18.5 kg/m2

BMI and Overall Survival in Advanced NSCLC Patients

Dahlberg SE, et al. J Thorac Oncol. 2013 Sep;8(9):1121-7.

Computerized Tomography: An Opportunistic Method

Subcutaneous adipose tissue

Visceral adipose tissue

Intermuscular adipose tissue

Skeletal muscle

Baracos V, et al. Int J Biochem Cell Bio. 2013;45(10):2302-2308.

Muscle Wasting in Cancer: A Hidden Condition

Prado CM, et al. Curr Opin Support Palliat Care. 2009 Dec;3(4):269-75.

SARCOPENICNORMAL

Same BSA = 2.07 and BMI = 30.3

0

20

40

60

80

100

120

0

20

40

60

80

100

120

140

160

10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54

Prev

alen

ce sa

rcop

enia

(%

)

Coun

t (N

)

Body mass index (kg/m2)

Prevalence of Low Muscle Mass in Patients with Solid Tumors of the Lung or Gastrointestinal Tract, N = 1476

Consecutive patients referred to a medical oncology service in a regional cancer center in Alberta, Canada.

Unpublished data from VE Baracos .

Sarcopenic Obesity: Prevalence of Physical Impairment

Sarcopenic obese

Non sarcopenic obese

P = 0.005

47%

26%

Prado CM, et al. Lancet Oncol. 2008 Jul;9(7):629-35.

Survival and Sarcopenic Obesity

Prado CM, et al. Lancet Oncol. 2008 Jul;9(7):629-35.

p <0.0001

Sarcopenic patients: 11.3 monthsNon-sarcopenic obese: 21.6 months

Non-sarcopenic obese

Sarcopenic obese

HR 2.3, P = 0.022

• Functional status

• Cancer type

•Stage of disease

• Age

• Gender

• History of weight loss

•Prado CM, et al. Lancet Oncol. 2008 Jul;9(7):629-35• Prado CM, et al. Int J Body Comp Research. 2010;8(1):7-

15

SURVIVAL

•Prado CM, et al:•Clin Cancer Res. 2007 Jun 1;13(11):3264-8•Clin Cancer Res. 2009 Apr 15;15(8):2920-6•Cancer Chemother Pharmacol. 2011 Jan;67(1):93-101

•Antoun S, et al. Ann Oncol. 2010 Aug;21(8):1594-8TOXICITY

•Prado CM, et al. Clin Cancer Res. 2009 Apr 15;15(8):2920-6TIME TO

TUMOR PROGRESSION

And physical disability, infections, complications during hospitalization, length of hospital stay, etc.

Sarcopenia (Severe Muscle Wasting) Predicts Key Health Outcomes

• Muscle wasting is common in lung cancer patients regardless of body weight • Cancer induced wasting begins early in the course of malignancy• Up to 50% of lung cancer patients have severe muscle wasting at diagnosis

Muscle Wasting in Lung Cancer Patients

Baracos VE, et al. Am J Clin Nutr. 2010 Apr;91(4):1133S-1137S. Bruera E. BMJ. 1997 ;8;315(7117):1219- 22. Schootman M, et al. Cancer. 2009 Nov 15;115(22):5329-38. Braithwaite D, et al. J Natl Cancer Inst. 2010 Oct 6;102(19):1468-77. Prado CM, et al. Lancet Oncol. 2008 Jul;9(7):629-35.

Prevalence of Cachexia Among Patients with Solid and Hematologic Malignancies at a National Cancer Institute (NCI) Designated Cancer Center

During the 12 Months Preceding Death- E. Del Fabbro, N. Skoro, B. Cassel

MASCC 2014PARALLEL SESSION: CACHEXIA & FATIGUE 2

Saturday, June 28, 2014

Loss of Muscle Mass Impairs Physical Function and Metabolic & Immunologic

Health

ProteinStores

Changes inenzymes,peptide

hormones,antibodies andcytokines, etc

Immunity

Impaired immunityand ineffective

antitumor response

Metabolism

Insulinresistance

MobilityDisability

Physicalperformance

AnorexiaFatigue

QOL

Weakness

Musclestrength

Disease

Muscle mass IndependenceHospitalization

Response to chemoTolerability to chemo

Mortality

Fearon KC, et al. Cell Metab. 2012 Aug 8;16(2):153-66.

1. Interfere with atrophy signaling• Myostatin /activin inhibitors• Anti-TNFα• Anti- IL-6

Therapeutic Approaches to Muscle Wasting

2. Stimulate hypertrophy signaling• Ghrelin mimetics/GH

secretagogues• Androgenic anabolic steroids /

SARMs

Targeting Muscle Wasting vs Cancer Cachexia

Product Description/MOA

Stage(Indication)

Last Reported Activity Comments

Enobosarm(GTx-024)

Selective Androgen Receptor Modulator

(SARM)

Phase III(prevention and

treatment of muscle wasting in NSCLC)

Aug 2013 Two phase III pivotal, international studies Topline results reported Aug 2013

Anamorelin(RC-1291) Ghrelin receptor agonist

Phase III(anorexia/ cachexia in

NSCLC)Sept 2013 Two phase III studies completed enrollment

Fall 2013

MT-102Anabolic catabolic transforming agent

(ACTA)

Phase II(cachexia) April 2012 Initiated Phase II multinational study in Mar

2011, est. completion June 2013

Macimorelin(AEZS-130)

Growth hormone secretagogue (GHS)

Phase IIa(cancer cachexia) Sept 2012

Phase IIa study initiated under a cooperative agreement with the DeBakey VA Med Ctr in Mar 2012

APD209Fixed combination of

progestin and selective β2-agonist

Phase II(cancer cachexia) Dec 2011

Results of a Phase IIa pilot study in 7 patients were presented at the Cachexia Conference in Milan, Dec 2012

BYM338Human HuCAL-based

antibody targeting ActRIIB

Phase II(cancer cachexia) Sept 2012

Initiated Phase II trial in patients with Stage IV NSCLC and Stage III/IV pancreatic cancer in Aug 2011. Currently enrolling

LY2495655 Anti-myostatin monoclonal antibody

Phase I/II(cancer cachexia and

disuse muscle atrophy)

July 2013 Phase II study in pancreatic cancer dose-escalation study est. compl. July 2014

The Role of Ghrelin in Anorexia-Cachexia Syndromes

Guillory B. Vitam Horm. 2013;92:61-106.Currow DC and Abernethy AP. Future Oncol. 2014 Apr;10(5):789-802.

• Ghrelin – The “hunger hormone”

• Stimulates food intake

• Stimulates release of GH/IGF-1 increase

• Decreases inflammatory cytokines

Anamorelin for the Treatment of Anorexia-Cachexia in NSCLC

Phase III Randomized, Double Blind, Placebo Controlled Trials

Eligibility

• Stage III/IV NSCLC

• Weight loss > 5% body weight or

• BMI < 20 kg/m2

Co-Primary Endpoints at 12 weeks

• Lean Body Mass by DXA scan

• Muscle Strength by Hand Grip Strength

D. CurrowMASCC 2014

PARALLEL SESSION: CACHEXIA & FATIGUE 2Saturday, June 28, 2014

SARM – Selective Androgen Receptor Modulator

The AR is a ligand-dependent transcription factor

Benefits• Increase muscle mass and strength• Increase bone mass• Positive effects on mood, energy

level, sense of well being and libido

Risks• Hirsutism and virilization (women)• Prostate hyperplasia (men)• Polycythemia• Decrease in serum HDL cholesterol• Elevations in transaminases

(oral androgens)

Benefits and risks of androgens

AR-DNA interaction

AR-Protein interactionHSP

AR a b c . . . . genes

Androgen

a b c . . . . genes

SARM

Androgen orSARM

Crawford J. Results from two Phase 3 randomized trials of enobosarm, selective androgen receptor modulator (SARM), for the prevention and treatment of muscle wasting in NSCLC. Presented at the European Cancer Congress, September 28, 2013, Amsterdam, Netherlands. Late Breaking Abstract 21.Mohler ML, et al. J Med Chem. 2009;52(12):3597-3617.

International Pivotal Phase III Clinical Trials: POWER 1 and POWER 2

Indication: Prevention and treatment of muscle wasting in patients with NSCLCStage III/IV NSCLC patients at initiation of 1st line chemotherapy

150 patients

150 patients

150 patients

Primary endpoints @ Day 84• Lean body mass DEXA• Physical function SCP

Placebo

Enobosarm 3 mg

Secondary endpoints• Durability of effect @ Day 147 • Overall survival (safety analysis)

POWER 1Platinum +

taxane

POWER 2platinum + non-taxane

Day 84 Day 147 Observation for vital status

SCP screening, baseline (Day 0), Day 42, Day 84 and Day 147DEXA baseline (Day 0), Day 42, Day 84 and Day 147

150 patients

150 patients

Efficacy Assessments

Placebo

Enobosarm3 mg

Crawford J et al. Presented at the European Cancer Congress. September 28, 2013. Amsterdam, Netherlands. Late Breaking Abstract 21.

Clinical Practice Guidelines on Cancer Cachexia

Consensus Recommendations

Enteral nutritional therapy Yes

Parenteral nutritional therapy

No

Supplements Insufficient data

Non-pharmacologic therapy Yes

Nutritional counseling Yes

Psychotherapeutic interventions

Yes (QOL)

Physical training Yes

European Palliative Care Research Collaborative. Clinical Practice Guidelines on Cancer Cachexia in Advanced Cancer Patients with a Focus on Refractory Cachexia – European Clinical Guidelines. Available at: www.epcrc.org/publication_listfiles.php?id=mWdBCMI5eXVlcNFk7Gnq. 2011

Pharmacologic Therapy Consensus Recommendations

Thalidomide Insufficient data

Cannabinoids May increase appetite

Omega-3-fatty acids Insufficient data

Megestrol/progestins Stimulate appetite + increase weight, but not

muscleSteroids Yes (short term)

Anti-inflammatory agents Little benefit

Prokinetics Yes, for GI symptoms



Consensus Recommendations

Anticancer therapy Can be beneficial or detrimental

Multimodal therapy(nutrition, physical training, medications)

Yes (but more research needed)

Prophylaxis for patients at risk

Nutritional counselingPhysical training

Yes (but little data)



• Nutrition in Cancer Care (PDQ®)• Health Professional Version• National Cancer Institute• Last Updated 2/26/2014

Useful Resource for Health Professionals

Conclusions• Cancer cachexia is prevalent at diagnosis and increases in

frequency and severity during the disease and treatment course of our patients

• Muscle wasting/sarcopenia is central to cancer cachexia, both at the molecular and clinical level and impacts function/QOL, treatment response/toxicity and survival

• Non-pharmacologic approaches with nutritional counseling and physical training, as well as selective pharmacologic interventions can be helpful in current management

• Promising approaches for earlier detection and monitoring, as well as new agents for treating cachexia/sarcopenia are under study

Mitigating Chemotherapy-Induced Constipation / Diarrhea in Newly Diagnosed CRC

Dorothy MK Keefe, PSM, MBBS, MD, FRACP, FRCPUniversity of Adelaide

• Balance between− oral intake− secretions into gastrointestinal tract− fluid re-absorption in the gastrointestinal tract− (metabolism)

• Varies between 3 times daily and once every 3 days

• Consistency also important• Normal volume depends on diet

Normal Bowel Function

NCI Common Toxicity Criteria

Diarrhea Increase of < 4 stools per day over baseline; mild increase in ostomy output compared to baseline; not interfering with ADL

Increase of 4–6 stools per day over baseline; IV fluids indicated < 24 hrs; moderate increase in ostomy output compared to baseline, not interfering with ADL

Increase of ≥ 7 stools per day over base-line; incontinence; IV fluids ≥ 24 hrs; hospitalization; severe increase in ostomy output compared to baseline, interfering with ADL

Life-threatening consequences (eg hemodynamic collapse)

Death

Ileus, (functional obstruction of bowel, ie neuroconstipation)

Asymptomatic, radiographic findings only

Symptomatic altered GI function (eg altered dietary habits); IV fluids, tube feeding, or TPN indicated < 24 hrs

Symptomatic and severe altered GI function; IV fluids, tube feeding, or TPN indicated ≥ 24 hrs

Life-threatening consequences

Death

Constipation

Adverse Event

Occasional or intermittent symptom, occasional use of stool softeners, laxatives, dietary modification, or enema

Persistent symptoms with regular use of laxatives or enema indicated

Symptoms interfering with ADL: constipation with manual evacuation indicated

Life-threatening consequences (eg obstruction, toxic megacolon)

Death

21 3 4 5

Common Terminology Criteria for Adverse Events v 4.0. Available at http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf

Opposite Ends of a Continuum

Diarrhea • Increased frequency• Decreased consistency• ± blood• ± mucus

Constipation• Decreased frequency• Increased consistency• ± blood

OUT

Fluid Into and Out of the Adult Alimentary Tract in 24 Hours (ml)

IN

Small bowel 1500

TOTAL IN~ 9000ml

TOTAL Absorbed~ 8300ml

Stools estimated150ml

By mouth 2000

Salivary glands 1500

Stomach 2500Liver 500

Pancreas 1500

Colon 1300

Ileum 2000

DuodenumJejunum 5000

Which Anti-Cancer Agents Do What?

Diarrhea5-FluorouracilMethotrexateIrinotecanTaxanesMonoclonal antibodiesSmall molecule TKIsHormonal agentsAnd most agents that have been tested

ConstipationVinca AlkaloidsThalidomideHormonal agentsProbably others

ConstipationDiarrhea(Unlikely to have increased

intake)• Decreased oral

intake (dehydration)• Decreased motility

(increases time for re-absorption to occur)

• Autonomic neuropathy

• Increased re-absorption

• Blockage• Overtreated diarrhea• Anti-nauseants• Analgesics• Decreased exercise

• Decreased surface area of small bowel and colon (secretory)

• Increased motility (osmotic + secretory)

• Decreased enzyme activity (osmotic)

• Increased infective agents (infectious)

• Increased mucous secretions (exudative)

• Overtreated constipation

How Can Chemotherapy Alter the Balance?

Mechanism of Diarrhea

• Villous atrophy• Rebound hyperplasia• Excess mucus secretion• Infection• Transient lactose intolerance• Immune colitis

Gastrointestinal Syndrome• Constellation of symptoms (not limited to Irinotecan)

− Severe diarrhea− Nausea/vomiting− Anorexia− Abdominal cramping

• Accompanied by− Severe dehydration− Neutropenia− Fever− Electrolyte imbalance

Benson AB, et al. J Clin Oncol. 2004 Jul 15;22(14):2918-26.

Infectious Diarrhea• Chemotherapy patients are at increased risk of infection• Leaky tight junctions between cells allow bacterial

translocation• Bacteria can invade directly, and can kill enterocytes• Complex micro-organisms can cause intestinal

anaphylaxis (proteases, ROS, mast cells and phagocytes)

• Immunological mechanisms cause damage via PMNs, macrophage activation and T-lymphocytes

• However, very little evidence that chemotherapy actually causes infectious diarrhea

Diarrhea from Targeted Agents

• Very little mechanistic study even now• Poor understanding of natural history and

prevention or treatment• High risk of new drugs having major toxicity• Anastamotic leaking / breakdown complicates

situation• Immune colitis not fully understood• Animal models few and far between

Mechanisms of Constipation

• Very poorly defined• Often secondary to opioids / anti-emetics

rather than anti-cancer drugs• Vinca alkaloids via autonomic neuropathy

leading to gastrointestinal dysmotility• Thalidomide via neuropathy

Pathway for Treatment

• Requires understanding of underlying mechanism

• Remembering that the body has a limited response repertoire to insult

Pathway for Diarrhea & ConstipationHISTORY

AXR• Obstruction• Bowel wall

thickening

ACTION• Maintain hydration• Optimize motility of gut• Do you need to

– secretion– osmolality– treat infection

Current bowel function Duration of change• Frequency

(nocturnal?)• Consistency• Blood• Mucus• Color

Other symptoms• Nausea/vomiting• Oral intake – fluid

– solid

• Exacerbating features• Fever/chills• Abdominal pain

– location– nature

• Weight loss• Bloating

EXAMINATION• Stool frequency• Consistency• Color• Blood results

Culture

PATIENT STATUS• Hydration• Abdominal

examination• Bowel sounds• (Rectal

examination)• Temperature• Blood Pressure

“Normal” bowel function• Frequency• Consistency• Color

Drug treatment• Chemotherapy• Targeted agents• Analgesics• Antibiotics• Anti-emetics• Complementary &

alternative• Other

Treatment

Octreotide at least 100µg bd s/c

Consider antibiotics

Diarrhea

Reduce dairy intake

Re-hydrate(oral or IV fluids)

If no response

Ioperamide2 stat +

1 with each loose stoolMaximum 11/day

Gastrointestinal Syndrome

• Aggressive treatment of diarrhea• Addition of oral fluoroquinolone if

− Diarrhea persists >24 hours− ANC < 500 cells / microlitre (+ / - fever / diarrhea)− Fever + Diarrhea (+ / - neutropenia)

• Evidence for antibiotics is limited

Rothenberg ML, et al. J Clin Oncol. 2005 Dec 20;23(36):9265-74.

Immune Colitis

• Aggressive use of steroids• Some evidence for infliximab• May need surgical resection• Life-threatening toxicity

MicrolaxG & O enemaMovicol

TreatmentConstipation

Mild exercise if appropriate

Stool Softener

Bulking Agent

If no response

Enema

Maintain Adequate Hydration

Palliation of Constipation

• Bulking Agents• Lubricants• Anthracenes • Osmotic laxatives

Agents Under Investigation

Diarrhea• Glp-2 analogues• Immune globulins• Nutritional supplements

• Early work looking at TLR-4 pathway

Constipation• Methylnaltrexone

MASCC/ISOO Guidelines 2014Panel recommendations in favor of an intervention:

• Intravenous amifostine be used, at a dose of at least 340mg/m2, to prevent radiation proctitis in patients receiving radiation therapy (Level II evidence)

• Octreotide, at a dose of at least 100 mcg subcutaneously twice daily, be used to treat diarrhea induced by standard- or high-dose chemotherapy associated with hematopoietic stem cell transplant, if loperamide is ineffective (Level II evidence)

MASCC/ISOO Evidence-Based Clinical Practice Guidelines for Mucositis Secondary to Cancer Therapy V2.2014. Available at: http://www.mascc.org/assets/Guidelines-Tools/mascc%20isoo%20mucositis%20guidelines%20summary%201feb2014.pdf. Accessed June 2014.

Recommendations in Favor of an Intervention

• Intravenous amifostine be used to prevent esophagitis induced by concomitant chemotherapy and radiation therapy in patients with non-small cell lung carcinoma (III)

• Sucralfate enemas be used to treat chronic radiation-induced proctitis in patients with rectal bleeding (III)

• Systemic sulfasalazine, at a dose of 500 mg administered orally twice a day, be used to prevent radiation-induced enteropathy in patients receiving radiation therapy to the pelvis (II)

• Probiotics containing Lactobacillus species be used to prevent diarrhea in patients receiving chemotherapy and/or radiation therapy for a pelvic malignancy (III)

• Hyperbaric oxygen be used to treat radiation-induced proctitis in patients receiving radiation therapy for a solid tumor (IV)


Recommendations Against an Intervention

• Systemic sucralfate, administered orally, not be used to treat gastrointestinal mucositis in patients receiving radiation therapy for a solid tumor (I).

• 5-acetyl salicylic acid (ASA), and the related compounds mesalazine and olsalazine, administered orally, not be used to prevent acute radiation-induced diarrhea in patients receiving radiation therapy for a pelvic malignancy (I).

• Misoprostol suppositories not be used to prevent acute radiation-induced proctitis in patients receiving radiation therapy for prostate cancer (I).


Summary

• Diarrhea and constipation are common problems in cancer patients

• Etiology is often multi-factorial• Treatments are largely palliative• Targeted agents are complicating the

situation• More work is required on mechanisms and

mechanism-driven treatments

Bring it all Together: Symposium Pearls from the Chair

Egidio Del Fabbro, MD - CHAIR Virginia Commonwealth University

Bringing It All Together

• Individualized patient assessment 1,2

• A multidisciplinary approach 3,4 • Evidence based management 5,6

• Improved outcomes 7,8

1.Gioulbasanis Ann Oncol 2011. 2.Vigano J Acad Nutr Diet 2014. 3.Ravasco JCO 2005. 4.Del Fabbro J Pall Med 20115.Roila FAnn Oncol 2010 . 6. Davis JPSM 2010. 7.Mantovani Oncologist 2010. 8.Quinten Lancet Oncol 2009

Bringing It All Together

• Limitations of current therapies 1

• Unmet needs 2

• Opportunities for improvement 3,4

• Earlier is better 5,6

1.Ruiz-Garcia Cochrane 2013. 2.Donithireddy J Supp Oncol 2007. 3.Garcia Supp Care Cancer 2013. 4.Lundholm Cancer 2010. 5.Prado Am J Clin Nutr 2013. 6 Aapro Ann Oncol 2014

Disclaimer

Documents

Transcript of Disclaimer