Madalynn Neu, PhD, RNEllyn Matthews, PhD, RN

Paul Cook, PhD

Chronic Stress and Distress of Mothers of Children with Acute Lymphocytic Leukemia During

Maintenance Therapy

This research is supported by the UCDenver Colorado Clinical Translational Science Institute (CCTSI) Pilot Award (1UL1RR014780) and Clinical Translational Research Center (CTRC) Funding for cortisol assays, bioinformatics, nursing support

We would like to acknowledge the contributions of the research team:

◦ Flori Legette◦ Kimberlee Horst◦ Nancy Kipke◦ Nancy Waas◦ Ken Clevenger◦ Erin Hughes◦ Megan Duffy

◦ Mark Laudenslager, PhD◦ Tim Garrington, MD◦ Martin Reite, MD◦ Paul Cook, PhD◦ Janie Kappius◦ Ann Ribe◦ Jane Ambro◦ Lacey Felmlee

Most common malignancy in childhood; accounts for 75% of all childhood leukemias◦ (AML 23%, CML 2%)

3000 new cases annually in U.S. Peak incidence is 4 years of age Overall survival of 70-80%, approaches 90%

for standard or low risk patients◦ Age: >1 and <10 yo is favorable◦ WBC: <50,000 is favorable

Induction: Goal is remission- 4wks Consolidation: Treatment to spine - 4-8 wks Interim Maintenance: Rest phase- 6-8 wks Delayed Intensification: Reduces # of hiding

cells- 8 wks Maintenance:

◦ 2 years for females◦ 3 years for males

Dexamethasone orally 5 days every 4 weeks

Vincristine IV every 4 weeks

Mercaptopurine orally daily x 84 days

Oral methotrexate weekly

Intrathecal methotrexate every 12 weeks

Steroids: increased appetite, weight gain, fluid retention, mood swings

Vincristine: body aches, peripheral neuropathy

Mercaptopurine: nausea, low blood counts Methotrexate: nausea, low blood counts

Stress◦ Activation of HPA axis indicated by cortisol

levels◦ Self-reported stress

Distress◦ Anxiety◦ Depression

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Childhood cancer has been associated with disruption in family life (Aung, 2012; Gedaly-Duff et al., 2006; Sung et al., 2011; Tsimicalis et al., 2012).

Posttraumatic stress reported in ~ 25% of parents of children with cancer (Poder et al., 2008)

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Decrease in parents of children with cancer from diagnosis to posttreatment ◦ May still be present years post treatment (Best et al., 2001;

Boman et al., 2003)

Occur during entire course of treatment for cancer (Norberg et al., 2005; Masa’deh et al., 2012; von Essen et al., 2004

More severe at time of diagnosis than later during treatment (Vrijmoet-Wiersma, 2008)

More severe in complicated cancer than with ALL (Hoven et al., 2008

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Perception of stress or emotional arousal activates HPA axis Persons experiencingchronic stress may have lower daily cortisol levels and flatter diurnal slopes(Bicanic et al., 2012; Sriram et al., 2012; van Liempt et al., 2012)

Overall survival is very good (80- 90%) in children with ALL

Research suggests that high levels of parental stress and distress decrease from time of diagnosis to post-treatment in children with cancer –but some parents continue to experience stress even after treatment is completed.

Few studies have investigated physiologic stress and emotional stress and distress in mothers of children with ALL specifically during maintenance treatment.

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Examine the sleep/wake patterns, physiologic stress, and emotional stress and distress in mothers of children during maintenance treatment for ALL compared to matched controls H1: Mothers of children with ALL will display

greater insomnia compared to mothers of healthy children

H2: Mothers of children with ALL will display greater physiologic stress than mothers of healthy children

H3: Mothers of children with ALL will report more emotional stress and distress (anxiety, depression) than mothers of healthy children

Overall Study Purpose

Comparative Study Design

Mothers/children with ALL Recruited through the TCH hematology practice

with the assistance of clinicians and research partners, who screened potential participants

Mothers/healthy children Recruited from the community (ad, brochure, or

university email), and matched by gender and age Informed consent was obtained Mothers received $40 and children received $10 or

an equivalently-priced stuffed animal, disbursed at the completion of visit 2.

Sampling and Study Procedures

Maternal Inclusion and Exclusion Criteria Inclusion

◦ Greater than 18 years of age◦ Primary caregiver◦ Speak and write English

Exclusion◦ Serious, unstable physical illness◦ Major psychiatric disorder◦ Diagnosed sleep disorder◦ Steroid medication

Child Inclusion and Exclusion Criteria Inclusion

◦ Between 3 and 12 years of age◦ No concurrent illness or disability◦ Capable of consistently wearing actiwatch per

mother’s assessment

ALL Only◦ Currently receiving maintenance treatment for

ALL

Demographic and Medical History Form (Adult and Child)

Stress Salivary Cortisol Perceived Stress Scale (PSS)Psychological Hospital Anxiety and Depression Scale (HADS)Sleep Wrist Actigraphy Adult and Child Sleep Diary Insomnia Interview Schedule (Screening) Insomnia Severity Index (ISI) The Children’s Sleep Habits Questionnaire (CSHQ)

Measures

Mothers were given filter paper strips to collect saliva Strips in booklet marked with day and time of desired collection Mothers were asked to collect saliva

On awakening30 minutes after awakeningBefore eating lunch10 hours after awakening

Mothers◦ Avoided eating, smoking, or drinking anything but water one hour before collection◦ Recorded time of last vigorous exercise, medications taken,

and date of last menstrual period◦ Placed strip on tongue for ~ 10 sec until lower 2 inches of

paper were saturated, marked the date and time of sample and air-dried the paper.

Salivary Cortisol

Visit 1 Consent obtained before or during visit 1 Questionnaires administered Education provided about salivary cortisol

sampling, collection times confirmed Actiwatches applied to non-dominant wrists (child and mother) Education provided about the actiwatch and sleep diaries

  Visit 2 (~ one week after visit 1)

Actiwatches, diaries, and saliva booklets collected

Compensation provided

Overview of Visit 1 and 2

Hypotheses Measure / Analysis

H2: Mothers with ALL child will report greater overall stress than mothers of healthy children

Perceived Stress Scale (PSS)ANOVA controlling for covariates of income, employment, race

Salivary cortisolIndependent t-tests to compare cortisol AUC, slope, wake to 30 minutes

H3: Mothers with ALL child will report greater more emotional distress (anxiety, depression) than mothers of healthy children.

Hospital Anxiety and Depression Scale (HADS)ANOVA controlling for covariates of income, employment, race

Statistical Analysis: Aim 1

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Area Under the Curve (AUC)

AUC

Slope

Morning rise to 30 minutes after awakening

Amount of change in cortisol per hour. 

Results: Dyad EnrollmentCONTROLS

Eligible (n= 29)

9 RefusedReason given: • Child would not wear watch (6)• Too busy (2)• No reason given (1)

3 RefusedReason given: • Child would not wear watch (2)• Inadequate reimbursement (1)

Completed Study: n = 26Completed Study: n = 26

ALLEligible (n = 35)

Demographics ALL(n = 26)

Control(n = 26)

Chi-Square

Married N (%) 84.6% 73.9% ns

Non Hispanic 69.2% 87.0% ns

Race: White 76.0% 84.6% ns

Education: ≥College

50.0% 76.9% p = .044

Employed (PT+FT)*

Full time

Part time

Unemployed

46.2%

23.1%

23.1%

53.8%

69.2%

57.7%

11.5%

30.8%

ns

p = .039

Married N (%) 84.6% 73.9% ns

Results: Demographic Data Demographic ALL

(n = 26)Control(n = 26)

T-test

Age (mother) 33.0 yrs 35.7 yrs ns

Age of child 3-10 yrs Matched

Results: Perceived Stress Scale (PSS) (Mothers, n =

52)

ns

Results: Hospital Anxiety and Depression Scale

(HADS)

** p .003

Results: Percent of Participants with Scores 8 and

Above (cut-off) for (HADS)

Results: Salivary Cortisol AUC

(n = 52)

**p=.015

Nmol/L

Results: Salivary Cortisol Slope(n = 52)

ns

Results: Salivary Cortisol Wake to 30 Minutes (n = 52)

Nmol/L

ns

Even in maintenance treatment, emotional distress are significantly worse in mothers of children with ALL than in matched controls

Daily cortisol levels were lower in mothers of children with ALL than in matched controls, physiologically suggesting the presence of chronic stress

Consistent with previous literature, sleep disturbance affect stress and depression levels in mothers of children with cancer, even when the chance of complete cure is very high

Discussion/Conclusion

The control sample was more highly educated, more employed and wealthier than the ALL sample (These potential covariates did not correlate with primary outcomes)

Sample may have been too small to detect differences in some measures

Fathers were not included in this study Time in maintenance was variable (~1

month to close to 36 months)

Limitations

Research Conduct a larger study so that the effect of duration of

maintenance treatment on parent stress can better be determined

Thoroughly examine the qualitative data collected in this study to determine feasibility of stress intervention for mothers/parents of children with ALL during maintenance

Include father in subsequent research Practice

Understand that even when prognosis is very favorable and treatment is not in the intense phases, mothers of children with ALL may be experiencing stress Encourage mothers to discuss their feelings during

treatment visits

Future Directions