Original Report

Insomnia is present when there is repeated difficulty initiating or maintaining sleep or impairment in sleep quality that occurs despite adequate time and opportunity for sleep, and there is some form of daytime impairment as a result.¹⁰ Secondary insomnia is denoted when insomnia is prominent and develops in the setting of another primary medical or psychiatric illness or in the setting of a separate sleep disorder such as sleep apnea.^{[10], [11] and [12]} Sleep disturbance can be associated with poor work performance, increased anxiety and depression, poor cognitive functioning, and impairment of overall quality of life (QOL).^{[13], [14], [15] and [16]} A recent Institute of Medicine report highlighted the severe costs to individuals and society of untreated insomnia.¹⁷

Davidson and colleagues² conducted a cross-sectional descriptive study in six malignant disease clinics from a regional cancer center in Canada. Those surveyed included patients with breast, gastrointestinal, gynecological, genitourinary, lung, and nonmelanoma skin cancers. Insomnia was defined as a report of trouble sleeping on at least 7 of the previous 28 nights, interfering with daytime functioning. More patients who had treatment within the past 6 months reported insomnia, use of sleeping pills, sleeping more than usual, or fatigue. There were no differences based on type of cancer or treatment. Baker and colleagues¹⁸ surveyed 752 adult patients who had been diagnosed with 1 of the 10 most commonly occurring cancers to identify which problems cancer survivors experience in dealing with their cancer and its treatment 1 year after diagnosis. Sleep difficulties ranked fifth on the list and were reported by 48% of the sample.

Fatigue is related to sleep disturbance. Although cancer-related fatigue is not necessarily relieved by sleep or rest, insomnia and sleep disturbances clearly contribute to fatigue issues. Fatigue and sleep disturbances are undoubtedly interwoven symptoms and may be difficult to separate. It is not known how much variance in fatigue is explained by sleep problems or in what situations sleep is a major contributor.

Pharmacological Treatments for Insomnia

Because sleep complaints are common, hypnotics are among the most commonly prescribed medications for cancer patients, being prescribed for insomnia in up to 44% of patients.¹⁹ Agents most commonly used are benzodiazepine receptor agonists, including true benzodiazepines, such as flurazepam, triazolam, quazepam, estazolam, and temazepam, and the nonbenzodiazepine agents zolpidem (Ambien^®), zaleplon (Sonata^®), and eszopiclone (Lunesta^®), which decrease subjective time to sleep onset, improve sleep efficiency, decrease the number of awakenings, and increase total sleep duration.^{[20], [21], [22] and [23]} Eszopiclone, extended-release formulations of zolpidem (Ambien), and ramelteon (a melatonin receptor agonist) are approved for prolonged use in patients with chronic insomnia;²⁴ but other hypnotics lack well-established effectiveness and safety data for use beyond brief intervals in situational insomnia or as part of a combined approach using cognitive-behavioral therapy (CBT) and brief pharmacological therapy.

In general, improvements in various sleep end points with pharmacologic therapy have been modest, with mean differences in sleep latency being about 15 minutes, wake after sleep onset improving by about 26 minutes, and total sleep time improving by about 40 minutes.^{[22], [24] and [25]} Although subjective improvements are often noted, hypnotic medications are associated with a number of risks, including residual next-day hypersomnia, dizziness, lightheadedness, impaired mental status, and increased risk of falls and hip fractures, especially in elderly patients when taking longer-acting hypnotics.^{[26], [27], [28], [29], [30] and [31]} Clearly, better options to improve sleep are still needed.

The Use of Valeriana officinalis for Sleep

Valeriana officinalis is a perennial herb found in North America, Europe, and Asia. In the United States, it is primarily sold as a sleeping aid, while in Europe it is used for restlessness, tremors, and anxiety. There are three main chemicals that are thought to be the active components of the plant. These are the essential oils valerenic acid and valenol, valepotriates, and a few alkaloids. Herbal extracts of V. officinalis can be ground root, aqueous or aqueous-alcoholic extracts using 70% ethanol and herb-to-extract ratios of 4–7:1. Single recommended doses range from 400 to 900 mg at bedtime.³² Most sleep studies have used 400 or 450 mg for their trials, with a couple of dose-finding trials showing that 900 mg was not significantly better than 450 mg.^{[33] and [34]} The main impact of valerian from those studies has been on sleep latency (time to fall asleep), and this has improved more in patients who had reported a longer time to fall asleep and who considered themselves poor sleepers.^{[33], [34], [35], [36] and [37]}

Most reviews proclaim V. officinalis to be a safe herb with no drug interactions, the only adverse event being daytime sedation at higher doses.^{[38] and [39]} Anecdotal reports of side effects include headaches, nausea, heart palpitations, and benzodiazepine-like withdrawal symptoms when stopping the agent.⁴⁰ Some concern has been raised as to whether valerian might interfere with cytochrome P-450 metabolism. An article by Budzinski and colleagues reviews numerous herbs and quantitates their interaction with cytochrome P-450.⁴¹ Out of 21 herbs tested, V. officinalis ranked at the bottom of interaction potential, rating a 15 out of a possible 16 (1 being the highest, 16 being the lowest).

The cost of V. officinalis, compared to other prescription sleep aids, is less, with a 1-month supply costing around $10 per month. By contrast, zolpidem, for example, costs over $80 per month.

Therefore, based on the favorable toxicity profile, low cost, and promising but limited pilot data, this current trial was designed to evaluate 450 mg of valerian at bedtime for sleep disturbance.

Methods

The primary purpose of this trial was to assess the effect of a standardized preparation of valerian in improving sleep in patients undergoing therapy for cancer. Secondary goals were to assess its safety as well as effect on anxiety, fatigue, and activities of daily living.

Patients eligible for this trial included adults diagnosed with cancer and receiving therapy (radiation, chemotherapy, oral antitumor agents, or endocrine therapy). Patients had to report difficulty sleeping of 4 or more on a scale of 0–10, had to have a life expectancy ≥6 months, and had to have an Eastern Cooperative Oncology Group (ECOG) performance score (PS) of 0 or 1. They could not have an abnormally elevated serum glutamic-oxaloacetic transaminase (SGOT) and/or alkaline phosphatase. Patients were excluded for prior use of valerian for sleep, use of other prescription sleep aids in the past 30 days, or a diagnosis of obstructive sleep apnea or primary insomnia per Diagnostic and Statistical Manual, 4th edition (DSM-IV), criteria. Pregnant and nursing women were also excluded, as were patients with known sleep disturbance etiologies such as nighttime hot flashes, uncontrolled pain, and/or diarrhea.

Participants were randomized to receive 450 mg of oral valerian or placebo, to be taken 1 hour before bedtime for 8 weeks. The valerian used was pure ground, raw root, from one lot and standardized to contain 0.8% valerenic acid. Valerian capsules and matching placebo, a gelatin capsule, were supplied by Hi-Health (Scottsdale, AZ). Both valerian and placebo were stored in the same containers so that the placebo would acquire some of the valerian smell. Self-report booklets were completed at baseline and at weeks 4 and 8 and contained the Pittsburgh Sleep Quality Index (PSQI),⁴² the Profile of Moods States (POMS),⁴³ the Functional Outcomes of Sleep Questionnaire (FOSQ),⁴⁴ and the Brief Fatigue Inventory (BFI).⁴⁵ Assessments were scored according to the appropriate algorithms, and total and subscale scores were transformed to a 0–100 scale, with 100 being best. Self-reported symptoms were recorded weekly using a self-report numeric analogue scale, called the Symptom Experience Diary (SED). Toxicity was also assessed every 2 weeks during a clinical research associate/nurse phone call using the Common Terminology Criteria for Adverse Events (CTCAE, v 3.0).

The primary end point was the normalized (averaged) area under the curve (AUC) of the PSQI between the two arms, compared using the Kruskal-Wallis test. Secondary analyses compared AUC scores of other assessments and toxicity incidence. Toxicity comparisons were performed using the chi-squared test or the Kruskal-Wallis test, as appropriate. As an intent-to-treat (ITT) analysis, using chi-squares tests, patients were categorized as a success if there was a 10-point improvement in the assessment score at week 4 or 8 and a failure if there was no improvement or data were missing.

All hypothesis testing was carried out using a two-sided alternative hypothesis and a 5% Type I error rate. A two-sample t-test with 100 patients per group provided 94% power to detect 50% times the standard deviation (SD) of the end point under study.⁴⁶ This effect size is considered moderate and has been declared the minimally clinically significant difference for QOL end points.^{[47] and [48]}

Results

A total of 227 patients were randomized into this study between March 19, 2004, and March 9, 2007. The consort diagram depicts the flow of data (Figure 1). Twenty-three patients withdrew before starting the study treatment. Primary end-point data were available on 119 patients (62 receiving valerian and 57 receiving placebo). Baseline characteristics and baseline patient reported outcomes were well balanced between arms with no statistically significant differences ([Table 1] and [Table 2]).

Insomnia is present when there is repeated difficulty initiating or maintaining sleep or impairment in sleep quality that occurs despite adequate time and opportunity for sleep, and there is some form of daytime impairment as a result.¹⁰ Secondary insomnia is denoted when insomnia is prominent and develops in the setting of another primary medical or psychiatric illness or in the setting of a separate sleep disorder such as sleep apnea.^{[10], [11] and [12]} Sleep disturbance can be associated with poor work performance, increased anxiety and depression, poor cognitive functioning, and impairment of overall quality of life (QOL).^{[13], [14], [15] and [16]} A recent Institute of Medicine report highlighted the severe costs to individuals and society of untreated insomnia.¹⁷

Davidson and colleagues² conducted a cross-sectional descriptive study in six malignant disease clinics from a regional cancer center in Canada. Those surveyed included patients with breast, gastrointestinal, gynecological, genitourinary, lung, and nonmelanoma skin cancers. Insomnia was defined as a report of trouble sleeping on at least 7 of the previous 28 nights, interfering with daytime functioning. More patients who had treatment within the past 6 months reported insomnia, use of sleeping pills, sleeping more than usual, or fatigue. There were no differences based on type of cancer or treatment. Baker and colleagues¹⁸ surveyed 752 adult patients who had been diagnosed with 1 of the 10 most commonly occurring cancers to identify which problems cancer survivors experience in dealing with their cancer and its treatment 1 year after diagnosis. Sleep difficulties ranked fifth on the list and were reported by 48% of the sample.

Fatigue is related to sleep disturbance. Although cancer-related fatigue is not necessarily relieved by sleep or rest, insomnia and sleep disturbances clearly contribute to fatigue issues. Fatigue and sleep disturbances are undoubtedly interwoven symptoms and may be difficult to separate. It is not known how much variance in fatigue is explained by sleep problems or in what situations sleep is a major contributor.

Pharmacological Treatments for Insomnia

Because sleep complaints are common, hypnotics are among the most commonly prescribed medications for cancer patients, being prescribed for insomnia in up to 44% of patients.¹⁹ Agents most commonly used are benzodiazepine receptor agonists, including true benzodiazepines, such as flurazepam, triazolam, quazepam, estazolam, and temazepam, and the nonbenzodiazepine agents zolpidem (Ambien^®), zaleplon (Sonata^®), and eszopiclone (Lunesta^®), which decrease subjective time to sleep onset, improve sleep efficiency, decrease the number of awakenings, and increase total sleep duration.^{[20], [21], [22] and [23]} Eszopiclone, extended-release formulations of zolpidem (Ambien), and ramelteon (a melatonin receptor agonist) are approved for prolonged use in patients with chronic insomnia;²⁴ but other hypnotics lack well-established effectiveness and safety data for use beyond brief intervals in situational insomnia or as part of a combined approach using cognitive-behavioral therapy (CBT) and brief pharmacological therapy.

In general, improvements in various sleep end points with pharmacologic therapy have been modest, with mean differences in sleep latency being about 15 minutes, wake after sleep onset improving by about 26 minutes, and total sleep time improving by about 40 minutes.^{[22], [24] and [25]} Although subjective improvements are often noted, hypnotic medications are associated with a number of risks, including residual next-day hypersomnia, dizziness, lightheadedness, impaired mental status, and increased risk of falls and hip fractures, especially in elderly patients when taking longer-acting hypnotics.^{[26], [27], [28], [29], [30] and [31]} Clearly, better options to improve sleep are still needed.

The Use of Valeriana officinalis for Sleep

Valeriana officinalis is a perennial herb found in North America, Europe, and Asia. In the United States, it is primarily sold as a sleeping aid, while in Europe it is used for restlessness, tremors, and anxiety. There are three main chemicals that are thought to be the active components of the plant. These are the essential oils valerenic acid and valenol, valepotriates, and a few alkaloids. Herbal extracts of V. officinalis can be ground root, aqueous or aqueous-alcoholic extracts using 70% ethanol and herb-to-extract ratios of 4–7:1. Single recommended doses range from 400 to 900 mg at bedtime.³² Most sleep studies have used 400 or 450 mg for their trials, with a couple of dose-finding trials showing that 900 mg was not significantly better than 450 mg.^{[33] and [34]} The main impact of valerian from those studies has been on sleep latency (time to fall asleep), and this has improved more in patients who had reported a longer time to fall asleep and who considered themselves poor sleepers.^{[33], [34], [35], [36] and [37]}

Most reviews proclaim V. officinalis to be a safe herb with no drug interactions, the only adverse event being daytime sedation at higher doses.^{[38] and [39]} Anecdotal reports of side effects include headaches, nausea, heart palpitations, and benzodiazepine-like withdrawal symptoms when stopping the agent.⁴⁰ Some concern has been raised as to whether valerian might interfere with cytochrome P-450 metabolism. An article by Budzinski and colleagues reviews numerous herbs and quantitates their interaction with cytochrome P-450.⁴¹ Out of 21 herbs tested, V. officinalis ranked at the bottom of interaction potential, rating a 15 out of a possible 16 (1 being the highest, 16 being the lowest).

The cost of V. officinalis, compared to other prescription sleep aids, is less, with a 1-month supply costing around $10 per month. By contrast, zolpidem, for example, costs over $80 per month.

Therefore, based on the favorable toxicity profile, low cost, and promising but limited pilot data, this current trial was designed to evaluate 450 mg of valerian at bedtime for sleep disturbance.

Methods

The primary purpose of this trial was to assess the effect of a standardized preparation of valerian in improving sleep in patients undergoing therapy for cancer. Secondary goals were to assess its safety as well as effect on anxiety, fatigue, and activities of daily living.

Patients eligible for this trial included adults diagnosed with cancer and receiving therapy (radiation, chemotherapy, oral antitumor agents, or endocrine therapy). Patients had to report difficulty sleeping of 4 or more on a scale of 0–10, had to have a life expectancy ≥6 months, and had to have an Eastern Cooperative Oncology Group (ECOG) performance score (PS) of 0 or 1. They could not have an abnormally elevated serum glutamic-oxaloacetic transaminase (SGOT) and/or alkaline phosphatase. Patients were excluded for prior use of valerian for sleep, use of other prescription sleep aids in the past 30 days, or a diagnosis of obstructive sleep apnea or primary insomnia per Diagnostic and Statistical Manual, 4th edition (DSM-IV), criteria. Pregnant and nursing women were also excluded, as were patients with known sleep disturbance etiologies such as nighttime hot flashes, uncontrolled pain, and/or diarrhea.

Participants were randomized to receive 450 mg of oral valerian or placebo, to be taken 1 hour before bedtime for 8 weeks. The valerian used was pure ground, raw root, from one lot and standardized to contain 0.8% valerenic acid. Valerian capsules and matching placebo, a gelatin capsule, were supplied by Hi-Health (Scottsdale, AZ). Both valerian and placebo were stored in the same containers so that the placebo would acquire some of the valerian smell. Self-report booklets were completed at baseline and at weeks 4 and 8 and contained the Pittsburgh Sleep Quality Index (PSQI),⁴² the Profile of Moods States (POMS),⁴³ the Functional Outcomes of Sleep Questionnaire (FOSQ),⁴⁴ and the Brief Fatigue Inventory (BFI).⁴⁵ Assessments were scored according to the appropriate algorithms, and total and subscale scores were transformed to a 0–100 scale, with 100 being best. Self-reported symptoms were recorded weekly using a self-report numeric analogue scale, called the Symptom Experience Diary (SED). Toxicity was also assessed every 2 weeks during a clinical research associate/nurse phone call using the Common Terminology Criteria for Adverse Events (CTCAE, v 3.0).

The primary end point was the normalized (averaged) area under the curve (AUC) of the PSQI between the two arms, compared using the Kruskal-Wallis test. Secondary analyses compared AUC scores of other assessments and toxicity incidence. Toxicity comparisons were performed using the chi-squared test or the Kruskal-Wallis test, as appropriate. As an intent-to-treat (ITT) analysis, using chi-squares tests, patients were categorized as a success if there was a 10-point improvement in the assessment score at week 4 or 8 and a failure if there was no improvement or data were missing.

All hypothesis testing was carried out using a two-sided alternative hypothesis and a 5% Type I error rate. A two-sample t-test with 100 patients per group provided 94% power to detect 50% times the standard deviation (SD) of the end point under study.⁴⁶ This effect size is considered moderate and has been declared the minimally clinically significant difference for QOL end points.^{[47] and [48]}

Results

A total of 227 patients were randomized into this study between March 19, 2004, and March 9, 2007. The consort diagram depicts the flow of data (Figure 1). Twenty-three patients withdrew before starting the study treatment. Primary end-point data were available on 119 patients (62 receiving valerian and 57 receiving placebo). Baseline characteristics and baseline patient reported outcomes were well balanced between arms with no statistically significant differences ([Table 1] and [Table 2]).

Insomnia is present when there is repeated difficulty initiating or maintaining sleep or impairment in sleep quality that occurs despite adequate time and opportunity for sleep, and there is some form of daytime impairment as a result.¹⁰ Secondary insomnia is denoted when insomnia is prominent and develops in the setting of another primary medical or psychiatric illness or in the setting of a separate sleep disorder such as sleep apnea.^{[10], [11] and [12]} Sleep disturbance can be associated with poor work performance, increased anxiety and depression, poor cognitive functioning, and impairment of overall quality of life (QOL).^{[13], [14], [15] and [16]} A recent Institute of Medicine report highlighted the severe costs to individuals and society of untreated insomnia.¹⁷

Davidson and colleagues² conducted a cross-sectional descriptive study in six malignant disease clinics from a regional cancer center in Canada. Those surveyed included patients with breast, gastrointestinal, gynecological, genitourinary, lung, and nonmelanoma skin cancers. Insomnia was defined as a report of trouble sleeping on at least 7 of the previous 28 nights, interfering with daytime functioning. More patients who had treatment within the past 6 months reported insomnia, use of sleeping pills, sleeping more than usual, or fatigue. There were no differences based on type of cancer or treatment. Baker and colleagues¹⁸ surveyed 752 adult patients who had been diagnosed with 1 of the 10 most commonly occurring cancers to identify which problems cancer survivors experience in dealing with their cancer and its treatment 1 year after diagnosis. Sleep difficulties ranked fifth on the list and were reported by 48% of the sample.

Fatigue is related to sleep disturbance. Although cancer-related fatigue is not necessarily relieved by sleep or rest, insomnia and sleep disturbances clearly contribute to fatigue issues. Fatigue and sleep disturbances are undoubtedly interwoven symptoms and may be difficult to separate. It is not known how much variance in fatigue is explained by sleep problems or in what situations sleep is a major contributor.

Pharmacological Treatments for Insomnia

Because sleep complaints are common, hypnotics are among the most commonly prescribed medications for cancer patients, being prescribed for insomnia in up to 44% of patients.¹⁹ Agents most commonly used are benzodiazepine receptor agonists, including true benzodiazepines, such as flurazepam, triazolam, quazepam, estazolam, and temazepam, and the nonbenzodiazepine agents zolpidem (Ambien^®), zaleplon (Sonata^®), and eszopiclone (Lunesta^®), which decrease subjective time to sleep onset, improve sleep efficiency, decrease the number of awakenings, and increase total sleep duration.^{[20], [21], [22] and [23]} Eszopiclone, extended-release formulations of zolpidem (Ambien), and ramelteon (a melatonin receptor agonist) are approved for prolonged use in patients with chronic insomnia;²⁴ but other hypnotics lack well-established effectiveness and safety data for use beyond brief intervals in situational insomnia or as part of a combined approach using cognitive-behavioral therapy (CBT) and brief pharmacological therapy.

In general, improvements in various sleep end points with pharmacologic therapy have been modest, with mean differences in sleep latency being about 15 minutes, wake after sleep onset improving by about 26 minutes, and total sleep time improving by about 40 minutes.^{[22], [24] and [25]} Although subjective improvements are often noted, hypnotic medications are associated with a number of risks, including residual next-day hypersomnia, dizziness, lightheadedness, impaired mental status, and increased risk of falls and hip fractures, especially in elderly patients when taking longer-acting hypnotics.^{[26], [27], [28], [29], [30] and [31]} Clearly, better options to improve sleep are still needed.

The Use of Valeriana officinalis for Sleep

Valeriana officinalis is a perennial herb found in North America, Europe, and Asia. In the United States, it is primarily sold as a sleeping aid, while in Europe it is used for restlessness, tremors, and anxiety. There are three main chemicals that are thought to be the active components of the plant. These are the essential oils valerenic acid and valenol, valepotriates, and a few alkaloids. Herbal extracts of V. officinalis can be ground root, aqueous or aqueous-alcoholic extracts using 70% ethanol and herb-to-extract ratios of 4–7:1. Single recommended doses range from 400 to 900 mg at bedtime.³² Most sleep studies have used 400 or 450 mg for their trials, with a couple of dose-finding trials showing that 900 mg was not significantly better than 450 mg.^{[33] and [34]} The main impact of valerian from those studies has been on sleep latency (time to fall asleep), and this has improved more in patients who had reported a longer time to fall asleep and who considered themselves poor sleepers.^{[33], [34], [35], [36] and [37]}

Most reviews proclaim V. officinalis to be a safe herb with no drug interactions, the only adverse event being daytime sedation at higher doses.^{[38] and [39]} Anecdotal reports of side effects include headaches, nausea, heart palpitations, and benzodiazepine-like withdrawal symptoms when stopping the agent.⁴⁰ Some concern has been raised as to whether valerian might interfere with cytochrome P-450 metabolism. An article by Budzinski and colleagues reviews numerous herbs and quantitates their interaction with cytochrome P-450.⁴¹ Out of 21 herbs tested, V. officinalis ranked at the bottom of interaction potential, rating a 15 out of a possible 16 (1 being the highest, 16 being the lowest).

The cost of V. officinalis, compared to other prescription sleep aids, is less, with a 1-month supply costing around $10 per month. By contrast, zolpidem, for example, costs over $80 per month.

Therefore, based on the favorable toxicity profile, low cost, and promising but limited pilot data, this current trial was designed to evaluate 450 mg of valerian at bedtime for sleep disturbance.

Methods

The primary purpose of this trial was to assess the effect of a standardized preparation of valerian in improving sleep in patients undergoing therapy for cancer. Secondary goals were to assess its safety as well as effect on anxiety, fatigue, and activities of daily living.

Patients eligible for this trial included adults diagnosed with cancer and receiving therapy (radiation, chemotherapy, oral antitumor agents, or endocrine therapy). Patients had to report difficulty sleeping of 4 or more on a scale of 0–10, had to have a life expectancy ≥6 months, and had to have an Eastern Cooperative Oncology Group (ECOG) performance score (PS) of 0 or 1. They could not have an abnormally elevated serum glutamic-oxaloacetic transaminase (SGOT) and/or alkaline phosphatase. Patients were excluded for prior use of valerian for sleep, use of other prescription sleep aids in the past 30 days, or a diagnosis of obstructive sleep apnea or primary insomnia per Diagnostic and Statistical Manual, 4th edition (DSM-IV), criteria. Pregnant and nursing women were also excluded, as were patients with known sleep disturbance etiologies such as nighttime hot flashes, uncontrolled pain, and/or diarrhea.

Participants were randomized to receive 450 mg of oral valerian or placebo, to be taken 1 hour before bedtime for 8 weeks. The valerian used was pure ground, raw root, from one lot and standardized to contain 0.8% valerenic acid. Valerian capsules and matching placebo, a gelatin capsule, were supplied by Hi-Health (Scottsdale, AZ). Both valerian and placebo were stored in the same containers so that the placebo would acquire some of the valerian smell. Self-report booklets were completed at baseline and at weeks 4 and 8 and contained the Pittsburgh Sleep Quality Index (PSQI),⁴² the Profile of Moods States (POMS),⁴³ the Functional Outcomes of Sleep Questionnaire (FOSQ),⁴⁴ and the Brief Fatigue Inventory (BFI).⁴⁵ Assessments were scored according to the appropriate algorithms, and total and subscale scores were transformed to a 0–100 scale, with 100 being best. Self-reported symptoms were recorded weekly using a self-report numeric analogue scale, called the Symptom Experience Diary (SED). Toxicity was also assessed every 2 weeks during a clinical research associate/nurse phone call using the Common Terminology Criteria for Adverse Events (CTCAE, v 3.0).

The primary end point was the normalized (averaged) area under the curve (AUC) of the PSQI between the two arms, compared using the Kruskal-Wallis test. Secondary analyses compared AUC scores of other assessments and toxicity incidence. Toxicity comparisons were performed using the chi-squared test or the Kruskal-Wallis test, as appropriate. As an intent-to-treat (ITT) analysis, using chi-squares tests, patients were categorized as a success if there was a 10-point improvement in the assessment score at week 4 or 8 and a failure if there was no improvement or data were missing.

All hypothesis testing was carried out using a two-sided alternative hypothesis and a 5% Type I error rate. A two-sample t-test with 100 patients per group provided 94% power to detect 50% times the standard deviation (SD) of the end point under study.⁴⁶ This effect size is considered moderate and has been declared the minimally clinically significant difference for QOL end points.^{[47] and [48]}

Results

A total of 227 patients were randomized into this study between March 19, 2004, and March 9, 2007. The consort diagram depicts the flow of data (Figure 1). Twenty-three patients withdrew before starting the study treatment. Primary end-point data were available on 119 patients (62 receiving valerian and 57 receiving placebo). Baseline characteristics and baseline patient reported outcomes were well balanced between arms with no statistically significant differences ([Table 1] and [Table 2]).

Although the perception of cognitive decline is a common complaint among individuals treated with chemotherapy, it is poorly understood and limited efforts have been made to identify the extent of this problem among women with ovarian cancer. To date, the few studies documenting the neuropsychological consequences of ovarian cancer and its treatment have shown that patients report cognitive problems but that these problems were not quantifiable using objective measures due to the lack of sensitivity of standard instruments to the subtle changes that occur during cancer treatment.^{[5], [6] and [7]}

Although studies of cognitive function among oncology patients have used instruments that have been validated in their own disciplines and with a variety of diseases, the evidence is emerging that they are not comprehensive or appropriate tools for the detection and evaluation of chemotherapy-related change in cognitive function.⁸ Furthermore, the likelihood of having these tests conducted in a similar manner across multiple institutions, sites, and interviewers with any degree of consistency is very low. This study was designed as a pilot study of the identification of chemotherapy-related changes in cognitive function among women with advanced ovarian cancer using a Web-based assessment tool (Headminder, Inc., New York, NY).⁷ The primary goal of the current study was to determine if there is evidence of changes in the cognitive function domains of attention, processing speed, and reaction time as well as self-reported changes in the memory, sensory-perception, and cognitive-intellectual domains of cognitive function during chemotherapy among women with newly diagnosed advanced ovarian cancer.

Materials and Methods

All study methods and procedures were reviewed and approved by the University of Arizona Institutional Review Board. Eligible patients included women with a histologically or pathologically confirmed diagnosis of stage III–IV epithelial ovarian or primary peritoneal cancer who were prescribed at least six courses of platinum-based therapy. Patients were excluded if they had a prior history of any cancer (other than nonmelanoma skin cancer), chemotherapy, radiation therapy, erythropoietin treatment (within the last 6 months), or severe head injury. Initially, patients were excluded if they received intraperitoneal therapy, but the protocol was later amended to permit the use of any platinum-based therapy, regardless of route of administration.

Assessment Tools

After providing informed consent, patients completed a neurocognitive battery of tests and the Functional Assessment of Cancer Therapy—Neurotoxicity (FACT-Ntx, to assess patient-reported neuropathy).^{[9] and [10]} The neurocognitive evaluation included both a computerized, Web-based and a patient-reported assessment. The Web-based assessment was provided by HeadMinders, Inc.^{[7] and [11]} and was a modified version of the Cognitive Stability Index. The modified battery was comprised of two warm-up tasks and three empirically-derived cognitive factors: Processing Speed (Animal Decoding and Symbol Scanning subtests), Attention (Number Recall and Number Sequencing subtests), and Reaction Time (Response Direction 1 and Response Direction 2 subtests). The subtests have been validated against traditional neuropsychological tests in healthy and clinical populations, including cancer patients.¹² Cognitive domain correlations in the battery's healthy normative sample range from 0.52 to 0.74, and correlations are similar or higher in clinical populations. Test–retest reliability of the factor scores between first and second administrations ranges from 0.74 to 0.82.¹² This Web-based neurocognitive assessment tool is 21 CFR Part 11– and Health on the Net (HON)–compliant to ensure patient confidentiality. Prior to undergoing the Web-based cognitive tests, all study participants completed a keyboard proficiency test as a “warm-up task” to the computerized assessment.

The patient-reported cognitive function tool used was the Patient Assessment of Own Functioning Scale (PAF).^{[13], [14] and [15]} The PAF includes eight scales that are grouped into the nature of the ability being considered. The Memory, Sensory-Perceptual, and Cognitive-Intellectual subscales of the PAF are included in this self-assessment questionnaire. Respondents are asked to rate on a six-point scale, from almost always to almost never, how often they experience a particular kind of difficulty in their everyday lives. For this study, the Memory and Cognitive-Intellectual subscales of the PAF were used, similar to other clinical research protocols investigating cognitive changes during chemotherapy treatment.¹⁵ The PAF has been shown to be directly related to the Minnesota Multiphasic Personality Inventory (MMPI)¹³ and to be highly correlated with other cognitive impairment indices, such as the American College of Rheumatology neuropsychology research battery of tests.¹⁶ Of note, self-reported cognitive change has not been shown to correlate formal assessments of cognitive function among individuals who have experienced cancer.^{[17], [18], [19], [20] and [21]}

The FACT-Ntx is a validated instrument^{[9] and [10]} that was used to evaluate neurotoxicity. This scale includes 11 items: nine to assess neurotoxicity, one to assess bodily weakness, and one to assess anemia. Neurotoxicity may affect a patient's ability to use the keyboard in the computerized neurocognitive evaluation. This complete assessment battery of tests was completed at baseline (within 5 days of initiation of chemotherapy) and again during follow-up assessments at cycle three and cycle six of chemotherapy. The medical record was reviewed and data were abstracted related to chemotherapy medications, all concomitant medications, and blood test results (eg, hemoglobin, CA-125).

Statistical Plan

This prospective study was exploratory in nature and designed to collect pilot data to determine if there is evidence of neurocognitive change in attention, processing speed, response time, or self-reported cognitive function during the course of chemotherapy among women being treated for advanced ovarian cancer. The purpose of this study was to obtain preliminary estimates of the incidence and degree of cognitive decline to aid in the planning of future studies. While prior estimates of cognitive function were not available for this population, power analyses demonstrate that with a target recruitment goal of 30 patients, a McNemar's test has 78% power at the 0.05 level of significance to detect a significant decline in impairment in a cognitive domain if 12 patients are found to have impairment prior to course six of treatment (but not at course three) and if as few as two patients demonstrate impairment prior to course three but not at course six. This study was therefore powered to detect declines in one or more of the domains that may have occurred at less than both of the study time points following the baseline assessment.

To be considered fully evaluable, patients had to have completed at least one follow-up neurocognitive evaluation and may not have received antipsychotic neuropsychological medications during the study (eg, chlorpromazine, haloperidol, clozapine). Antidepressants and antianxiety medications (eg, serotonin/norepinephrine reuptake inhibitors or benzodiazepines) were permitted and use was recorded throughout study participation. A summary score for each cognitive domain (processing speed, reaction time, and attention) was recorded at each assessment time point using the HeadMinder Web-based assessment. This summary score was assessed by time (processing speed and reaction time), measured to the hundredth of a second, and by number of errors (attention). If a cognitive domain summary score at a follow-up assessment time declined at least one standard error of measurement (SEM) from baseline, the patient was considered to have experienced a decline at that time point. For the purposes of this article, such declines are referred to as “impairments” within the cognitive domain under investigation. A cognitive index score (CIS) was calculated as the number of cognitive domains impaired for the time point. The range of a CIS is 0–3, with zero equal to no impairment on any cognitive domain and three equal to impairment on all cognitive domains. Patients with only one cognitive domain decline (CIS = 1) at any one of the follow-up assessment time points were considered as having possible cognitive function decline. Patients with more than one cognitive domain impairment (CIS >1) at any follow-up assessment time points were considered as having evidence of cognitive function decline. The incidence of cognitive function impairment was determined by the percentage of patients who experienced any cognitive domain impairment (including possible and evidence of decline) at any follow-up assessment.

A repeated-measures analyses of variance (ANOVA) was used to further explore the neurocognitive values at the various time points during the study. Many of the neurocognitive values were not normally distributed but skewed either positively or negatively, so the square roots of the values were used in the analyses. Since this is an exploratory analysis, no corrections for multiple comparisons were performed.

The patient-reported cognitive function instrument (PAF) contains items scored on a Likert-type scale from almost never to almost always (range 0–5). Patient-reported outcomes as measured with the PAF are measured as mean scale values, ranging from 0, indicating no impairment, to 5.0, indicating complete impairment. PAF score ranges indicate low (≤1.25), medium (1.26–1.92), and high (≥1.93) levels of cognitive impairment.¹³ A total FACT-Ntx score was obtained; lower scores represent greater neurotoxicity, ranging from 0 (extreme neurotoxicity) to 44 (no neurotoxicity). The total score was reported, with adjustments made for missing values as described elsewhere.²²

Results

Thirty patients were enrolled in this study; however, two were later deemed ineligible, and one was unable to complete the baseline neurocognitive assessment prior to chemotherapy and was withdrawn from the study, resulting in 27 patients available for assessment. Five of these patients did not complete all neurocognitive assessments. The primary reason for nonadherence to the study schedule was clinical scheduling (eg, chemotherapy was administered prior to the neurocognitive assessment). The characteristics of eligible patients are provided in Table 1. The majority of patients were receiving intravenous chemotherapy (intraperitoneal therapy was at first not permitted but later was allowable following an amendment to the protocol) and taking concomitant sleep, antianxiety, and/or antidepressant medications outside of every 3- to 4-week chemotherapy regimen (primarily zolpidem, lorazepam, sertraline, and/or trazodone).

Although the perception of cognitive decline is a common complaint among individuals treated with chemotherapy, it is poorly understood and limited efforts have been made to identify the extent of this problem among women with ovarian cancer. To date, the few studies documenting the neuropsychological consequences of ovarian cancer and its treatment have shown that patients report cognitive problems but that these problems were not quantifiable using objective measures due to the lack of sensitivity of standard instruments to the subtle changes that occur during cancer treatment.^{[5], [6] and [7]}

Although studies of cognitive function among oncology patients have used instruments that have been validated in their own disciplines and with a variety of diseases, the evidence is emerging that they are not comprehensive or appropriate tools for the detection and evaluation of chemotherapy-related change in cognitive function.⁸ Furthermore, the likelihood of having these tests conducted in a similar manner across multiple institutions, sites, and interviewers with any degree of consistency is very low. This study was designed as a pilot study of the identification of chemotherapy-related changes in cognitive function among women with advanced ovarian cancer using a Web-based assessment tool (Headminder, Inc., New York, NY).⁷ The primary goal of the current study was to determine if there is evidence of changes in the cognitive function domains of attention, processing speed, and reaction time as well as self-reported changes in the memory, sensory-perception, and cognitive-intellectual domains of cognitive function during chemotherapy among women with newly diagnosed advanced ovarian cancer.

Materials and Methods

All study methods and procedures were reviewed and approved by the University of Arizona Institutional Review Board. Eligible patients included women with a histologically or pathologically confirmed diagnosis of stage III–IV epithelial ovarian or primary peritoneal cancer who were prescribed at least six courses of platinum-based therapy. Patients were excluded if they had a prior history of any cancer (other than nonmelanoma skin cancer), chemotherapy, radiation therapy, erythropoietin treatment (within the last 6 months), or severe head injury. Initially, patients were excluded if they received intraperitoneal therapy, but the protocol was later amended to permit the use of any platinum-based therapy, regardless of route of administration.

Assessment Tools

After providing informed consent, patients completed a neurocognitive battery of tests and the Functional Assessment of Cancer Therapy—Neurotoxicity (FACT-Ntx, to assess patient-reported neuropathy).^{[9] and [10]} The neurocognitive evaluation included both a computerized, Web-based and a patient-reported assessment. The Web-based assessment was provided by HeadMinders, Inc.^{[7] and [11]} and was a modified version of the Cognitive Stability Index. The modified battery was comprised of two warm-up tasks and three empirically-derived cognitive factors: Processing Speed (Animal Decoding and Symbol Scanning subtests), Attention (Number Recall and Number Sequencing subtests), and Reaction Time (Response Direction 1 and Response Direction 2 subtests). The subtests have been validated against traditional neuropsychological tests in healthy and clinical populations, including cancer patients.¹² Cognitive domain correlations in the battery's healthy normative sample range from 0.52 to 0.74, and correlations are similar or higher in clinical populations. Test–retest reliability of the factor scores between first and second administrations ranges from 0.74 to 0.82.¹² This Web-based neurocognitive assessment tool is 21 CFR Part 11– and Health on the Net (HON)–compliant to ensure patient confidentiality. Prior to undergoing the Web-based cognitive tests, all study participants completed a keyboard proficiency test as a “warm-up task” to the computerized assessment.

The patient-reported cognitive function tool used was the Patient Assessment of Own Functioning Scale (PAF).^{[13], [14] and [15]} The PAF includes eight scales that are grouped into the nature of the ability being considered. The Memory, Sensory-Perceptual, and Cognitive-Intellectual subscales of the PAF are included in this self-assessment questionnaire. Respondents are asked to rate on a six-point scale, from almost always to almost never, how often they experience a particular kind of difficulty in their everyday lives. For this study, the Memory and Cognitive-Intellectual subscales of the PAF were used, similar to other clinical research protocols investigating cognitive changes during chemotherapy treatment.¹⁵ The PAF has been shown to be directly related to the Minnesota Multiphasic Personality Inventory (MMPI)¹³ and to be highly correlated with other cognitive impairment indices, such as the American College of Rheumatology neuropsychology research battery of tests.¹⁶ Of note, self-reported cognitive change has not been shown to correlate formal assessments of cognitive function among individuals who have experienced cancer.^{[17], [18], [19], [20] and [21]}

The FACT-Ntx is a validated instrument^{[9] and [10]} that was used to evaluate neurotoxicity. This scale includes 11 items: nine to assess neurotoxicity, one to assess bodily weakness, and one to assess anemia. Neurotoxicity may affect a patient's ability to use the keyboard in the computerized neurocognitive evaluation. This complete assessment battery of tests was completed at baseline (within 5 days of initiation of chemotherapy) and again during follow-up assessments at cycle three and cycle six of chemotherapy. The medical record was reviewed and data were abstracted related to chemotherapy medications, all concomitant medications, and blood test results (eg, hemoglobin, CA-125).

Statistical Plan

This prospective study was exploratory in nature and designed to collect pilot data to determine if there is evidence of neurocognitive change in attention, processing speed, response time, or self-reported cognitive function during the course of chemotherapy among women being treated for advanced ovarian cancer. The purpose of this study was to obtain preliminary estimates of the incidence and degree of cognitive decline to aid in the planning of future studies. While prior estimates of cognitive function were not available for this population, power analyses demonstrate that with a target recruitment goal of 30 patients, a McNemar's test has 78% power at the 0.05 level of significance to detect a significant decline in impairment in a cognitive domain if 12 patients are found to have impairment prior to course six of treatment (but not at course three) and if as few as two patients demonstrate impairment prior to course three but not at course six. This study was therefore powered to detect declines in one or more of the domains that may have occurred at less than both of the study time points following the baseline assessment.

To be considered fully evaluable, patients had to have completed at least one follow-up neurocognitive evaluation and may not have received antipsychotic neuropsychological medications during the study (eg, chlorpromazine, haloperidol, clozapine). Antidepressants and antianxiety medications (eg, serotonin/norepinephrine reuptake inhibitors or benzodiazepines) were permitted and use was recorded throughout study participation. A summary score for each cognitive domain (processing speed, reaction time, and attention) was recorded at each assessment time point using the HeadMinder Web-based assessment. This summary score was assessed by time (processing speed and reaction time), measured to the hundredth of a second, and by number of errors (attention). If a cognitive domain summary score at a follow-up assessment time declined at least one standard error of measurement (SEM) from baseline, the patient was considered to have experienced a decline at that time point. For the purposes of this article, such declines are referred to as “impairments” within the cognitive domain under investigation. A cognitive index score (CIS) was calculated as the number of cognitive domains impaired for the time point. The range of a CIS is 0–3, with zero equal to no impairment on any cognitive domain and three equal to impairment on all cognitive domains. Patients with only one cognitive domain decline (CIS = 1) at any one of the follow-up assessment time points were considered as having possible cognitive function decline. Patients with more than one cognitive domain impairment (CIS >1) at any follow-up assessment time points were considered as having evidence of cognitive function decline. The incidence of cognitive function impairment was determined by the percentage of patients who experienced any cognitive domain impairment (including possible and evidence of decline) at any follow-up assessment.

A repeated-measures analyses of variance (ANOVA) was used to further explore the neurocognitive values at the various time points during the study. Many of the neurocognitive values were not normally distributed but skewed either positively or negatively, so the square roots of the values were used in the analyses. Since this is an exploratory analysis, no corrections for multiple comparisons were performed.

The patient-reported cognitive function instrument (PAF) contains items scored on a Likert-type scale from almost never to almost always (range 0–5). Patient-reported outcomes as measured with the PAF are measured as mean scale values, ranging from 0, indicating no impairment, to 5.0, indicating complete impairment. PAF score ranges indicate low (≤1.25), medium (1.26–1.92), and high (≥1.93) levels of cognitive impairment.¹³ A total FACT-Ntx score was obtained; lower scores represent greater neurotoxicity, ranging from 0 (extreme neurotoxicity) to 44 (no neurotoxicity). The total score was reported, with adjustments made for missing values as described elsewhere.²²

Results

Thirty patients were enrolled in this study; however, two were later deemed ineligible, and one was unable to complete the baseline neurocognitive assessment prior to chemotherapy and was withdrawn from the study, resulting in 27 patients available for assessment. Five of these patients did not complete all neurocognitive assessments. The primary reason for nonadherence to the study schedule was clinical scheduling (eg, chemotherapy was administered prior to the neurocognitive assessment). The characteristics of eligible patients are provided in Table 1. The majority of patients were receiving intravenous chemotherapy (intraperitoneal therapy was at first not permitted but later was allowable following an amendment to the protocol) and taking concomitant sleep, antianxiety, and/or antidepressant medications outside of every 3- to 4-week chemotherapy regimen (primarily zolpidem, lorazepam, sertraline, and/or trazodone).