NEUROPROTECTIVE EFFECT OF PAROXETINE HYDROCHLORIDE AMONG 781 CANCER

PATIENTS RECEIVING CHEMOTHERAPY: A URCC CCOP STUDY.

Pascal Jean-Pierre, PhD, MPHUniversity of Rochester Medical Center

James P. Wilmot Cancer Center

Disclosures• No Conflict of Interest

• No relationship with GlaxoSmithKline

• This is an exploratory study

• Although hopeful, future studies need to replicate and/or extend the findings

Learning Objectives

• Describe the impact of cancer and cancer treatment on cognitive function (e.g., problems in attention, memory, and other aspects of cognitive function).

• Describe the neuroprotective effect of paroxetine hydrochloride, adjusting for depression, in cancer patients undergoing chemotherapy.

After reading and reviewing this material, the participant should be better able to:

Outline

• Definition of cognitive dysfunction in the present study

• Epidemiology of cancer-related cognitive dysfunction (CRCD)

• Pathophysiology of CRCD• Paroxetine hydrochloride vs. placebo

(adjusting for depression) for CRCD• Directions for future research

In the present study the term “cognitive dysfunction” is used to refer to cancer patient reported problems in attention and memory.

Definition

Cognitive dysfunction - Declining in mental processes underlying behavior

Mild Severe

Cognitive dysfunction - Declining in mental processes underlying behavior

Mild Severe

Cancer-Related Cognitive Dysfunction:

A significant problem for patients

Cancer and its

Treatments Problems in attention, memory and other aspects of neurocognitive

functioning Psychosocial functioning,

Quality of Life

17% to 75% of cancer patients reported problems in attention and memory during and following cancer treatment.

• Genetic predisposition

• Direct/indirect toxic effects of chemotherapy on the brain

• Effects of cancer chemotherapy on neurogenesis

• Issues with hormones (e.g., androgen deprivation therapy)

• Effects of cytokine activities in the brain

• Neuronal integrating and signaling activities

• Involvement of other symptoms

Pathophysiology and Current Theories of

Cancer-Related Cognitive Dysfunction (CRCD)

Key components of CRCD

• Impairment in attention– Focused attention– Divided attention

• Impairment in memory– Difficulty in memory retrieval– Restriction of working memory capacity

• Processing speed dysfunction– Change/conversion of information

• Executive dysfunction– Planning, decision-making, abstract thinking– Selection of relevant sensory information

Most Common clinical complaints: Difficulty multi-tasking, Difficulty concentrating, Generalized

slowing of cognitive function, Increased effort in mentation

Management of Cancer-related Cognitive Dysfunction

Paucity of relevant data on effective interventions for CRCD

Interventions Pharmacologic Non-pharmacologic

Memory Problems was assessed using a brief screening measure of attention and memory problems related to cancer (BSMAM-Ca)

Reliability Assessment revealed α = .90 for the BSMAM-Ca

PCA revealed a 1-component structure that explained 73% of the variance for the BSMAM-Ca

Depression assessed using the CES-D

Repeated measure ANOVA (r-ANOVA) and t-tests were conducted to assess changes in mean scores on the BSMAM-Ca Effects of (treatment) paroxetine hydrochloride versus (control) placebo

ANALYSES

Drug Placebo

Mean Age 56.5 years 56.3 yearsAge range 27 – 87 years 23 – 84 years

Female 80% 71%

Some College 55% 51%HS or less 45% 45%

Married 70% 71%

Breast Cancer 57% 50%Lung cancer 14% 13%Hematologic 12% 15%Gynecologic 7% 9%Gastroinstestinal 4% 9%other 6% 4%

SAMPLE CHARACTERISTICS

Having a diagnosis of cancer and were expecting to begin the first cycle of chemotherapy, were scheduled for at least four cycles of chemotherapy without concurrent radiation or interferon treatment,

At least 18 years of age and able to provide informed consent.

Day one of each chemotherapy cycle must have been separated by at least three weeks from day one of the next cycle.

Patients must have had adequate renal, hepatic, and cardiac function as determined by the treating oncologist.

Able to swallow Patients medication.

Had not been treated within the prior 14 days with psychotropic medication, monoamine oxidase inhibitors, or other drugs that increase brain serotonin concentrations (e.g., tryptophan).

Not currently pregnancy or nursing, no previous histories of mania, seizures, or hospitalization for any psychiatric condition, and no current treatment with warfarin (Coumadin®) for therapeutic anticoagulation.

Eligibility Criteria

PCA and Factor Loadings of BSMAM

My head feels heavy

I am apt to forget things

I cannot concentrate

It is difficult to think

My brain feels muddle

.92 BSMAM-Ca

.89

.68

.89

.84

Statistically significant difference in change scores from baseline (after first chemotherapy cycle, and before paroxetine) to follow-up (after four cycles of chemotherapy, after paroxetine). [F(1, 583) = 5.52, p = 0.02)]

Patients on paroxetine reported more improvement on attention and memory problems than patients on placebo (p < 0.05).

Paroxetine hydrochloride had a statistically significant effect after controlling for depression (p < 0.001).

FINDINGS

Baseline Follow-up

Drug M = 9.07, SD = 4.39 M = 8.20, SD = 3.77

Placebo M = 8.48, SD = 3.88 M = 8.10, SD = 3.57

Baseline Follow-up

Drug M = 9.07, SD = 4.39 M = 8.20, SD = 3.77

Placebo M = 8.48, SD = 3.88 M = 8.10, SD = 3.57

CLINICAL AND RESEARCH CHALLENGES

MemoryMemory

•Prefrontal cortex (WM/STM; Recall)• emotional regulation, decision making, • numerous connections with other parts important in mood regulation • low activity with depression

•Amygdala (WM/STM LTM)• rich in glucocorticoid receptors• particularly sensitive to stress

•Hippocampus (WM/STM LTM)• rich in glucocorticoid receptors• vulnerable to neural atrophy and decreased neurogenesis/cell proliferation under stressful conditions

•Prefrontal cortex (WM/STM; Recall)• emotional regulation, decision making, • numerous connections with other parts important in mood regulation • low activity with depression

•Amygdala (WM/STM LTM)• rich in glucocorticoid receptors• particularly sensitive to stress

•Hippocampus (WM/STM LTM)• rich in glucocorticoid receptors• vulnerable to neural atrophy and decreased neurogenesis/cell proliferation under stressful conditions

DepressionDepression

SSRI – Neural Stimulation – Cognitive Function

Antidepressant and environmental interventions that confer antidepressant

like behavior

Antidepressant and environmental interventions that confer antidepressant

like behavior

Improvement in attention, memory, and

other aspects of cognitive function

Improvement in attention, memory, and

other aspects of cognitive function

Stimulation of relevant brain components

Stimulation of relevant brain components

Cancer-related cognitive dysfunction is a serious problem for cancer patients and survivors

Patients on paroxetine hydrochloride reported greater improvement in cognitive function than those on placebo, even after controlling for depression

Summary

Conclusions• Paroxetine hydrochloride (PH) seems promising to

alleviating cancer-related cognitive dysfunction

• This preliminary data showed a statistically significant effect on PH on cancer-related cognitive dysfunction after controlling for depression

• Albeit very useful, this is a post hoc analysis and should be interpreted cautiously.

• Future studies should examine the usefulness of SSRI and other drugs

Central-Illinois CCOPColorado Cancer Research Program CCOPColumbia River CCOPColumbus CCOPDayton Clinical Oncology Program (DCOP)Evanston CCOPGreenville CCOPGrand Rapids CCOPGulf Coast MBCCOPHawaii MBCCOP

Hematology-Oncology of CNY CCOPKalamazoo CCOPKansas City CCOPMarshfield Clinic Research Foundation CCOPMetro-Minnesota CCOPNorth Shore University Hospital CCOPNorthwest CCOPSanta Rosa CCOP

Southeast Cancer Control ConsortiumSouthern Nevada CR Foundation CCOPUniversity of Illinois at Chicago MBCCOPUpstate Carolina CCOPVirginia Mason Research Center CCOPWestern Regional CCOPWichita CCOP

CCOPs

URCC

University of Rochester Cancer Center Community Clinical Oncology Program Research Base - Map of Affiliates (2008)

Newest Affiliates

Gary R. Morrow, PhD, MSSupriya Mohile, MD, MS

J. Bahrenberg, MDJ. Atkins, MDM. Weiss, MD