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Clinical note| Volume 23, ISSUE 5, P442-447, May 2002

An Open-Label, Crossover Trial of Mirtazapine (15 and 30 mg) in Cancer Patients with Pain and Other Distressing Symptoms

      Abstract

      We performed a pilot open-label, crossover trial of mirtazapine (15 and 30 mg at night) in advanced cancer patients with pain and other distressing symptoms. Twenty patients completed the trial and sixteen dropped out. Following a baseline assessment, patients completed a one-week observation period and were then randomized to a starting dose of either 15 mg or 30 mg of mirtazapine given at bedtime. After three weeks, subjects were switched to the alternate dose and followed by an additional three-week period, completing the treatment. The average age of the completers was 60.2 years and consisted of 7 women and 13 men. The majority were Caucasian (n = 18, 90%) and married (n = 18, 90%). The drop-out group did not significantly differ from the completers based on age, gender, race, marital status, or tumor type. We examined the impact of mirtazapine therapy on patients' levels of depression, pain intensity, appetite, insomnia, weight, and overall quality of life. A series of repeated measures ANOVAs were conducted to compare the completers' status at Weeks 1, 4, and 7 compared to baseline and to examine the interaction with starting dose and baseline observations. Scores on the Zung self-rating Depression Scale (F = 8.20, P < 0.05) and the Functional Assessment of Cancer Therapy – General Measure (F = 5.73, P < 0.05) were significantly improved at study end (Week 7) and were not dependent on mirtazapine dosage. Patients' weights were significantly higher at both Week 4 and Week 7, independent of dosage. Trend level differences were found on Memorial Pain Assessment Card items for pain, pain relief, and mood and on numeric rating scales measuring nausea, anxiety, insomnia, and appetite. This open-label pilot study suggests that mirtazapine may be effective for improving multiple symptoms, depression and quality of life in patients with advanced cancer. A controlled trial of this drug would be valuable.

      Keywords

      Introduction

      Thirty to fifty percent of cancer patients manifest significant affective disorders in the form of adjustment disorders or major depression.
      • Derogatis L.R
      • Morrow G.R
      • Fetting J
      • et al.
      The prevalence of psychiatric disorders among cancer patients.
      Given the negative impact of depression on social and vocational functioning,
      • Wells K.B
      • Stewart A
      • Hayes R.D
      • et al.
      The Functioning and Well-being of Depressed Patients Results from the Medical Outcomes Study.
      and the increased medical costs incurred when depression is a comorbid diagnosis of medical illness,
      • Simon J
      • Glazer W
      Carving in and Keeping Mental Health Care in the Managed Care Setting.
      it is an important target for study and treatment.
      As cancer patients live with their disease and its treatment, they often suffer with multiple distressing symptoms. In one study, ambulatory patients experienced almost ten symptoms, and inpatients averaged nearly 15.
      • Portenoy R
      • Thaler H
      • Kornblith A
      • et al.
      The Memorial Symptom Assessment Scale An instrument for the evaluation of symptom prevalence, characteristics, and distress.
      With so many symptoms characterizing the experience of these patients, oncology and palliative care specialists are faced with a need to be economical in their choices of drugs for symptom management. When choosing interventions for depression, for example, targeting multiple symptoms with a single drug can potentially improve quality of life, avoid polypharmacy and drug interactions, and not overly burden patients with extraordinarily complex regimens.
      Many antidepressants offer this possibility. While the trend in treating depression in physically healthy patients has turned toward “cleaner” drugs with minimal side effects, cancer patients often can benefit from an approach that “mobilizes” drug side effects for their potential benefit. Although there have been very few clinical trials of antidepressants, published data do suggest that a focus on symptom management offers the prospect of increased quality of life, less suffering, and continued social and vocational productivity as potential outcomes of treatment.
      • Holland J.C
      • Romano S.J
      • Heiligenstein J.H
      • et al.
      A controlled trial of fluoxetine and desipramine in depressed women with advanced cancer.

      Passik SD, Theobald DE, Lundberg J, et al. Initial results of an investigation of the effects of olanzapine for the relief of opioid-induced nausea in cancer pain patients, Midwest Pain Society 23rd Scientific Meeting, March 12–13, 1999, Chicago, IL.

      Passik SD, Theobald DE, Lundberg J, Donaghy K, Holtsclaw E, Kirsh K. The initial experiences with anti-depressant algorithm in a community based oncology clinic. Pan American Congress of Psychosocial and Behavioral Oncology, October 20–23, 1999, New York, NY.

      For example, in one of the very few controlled studies in the psycho-oncology literature, Holland and colleagues
      • Holland J.C
      • Romano S.J
      • Heiligenstein J.H
      • et al.
      A controlled trial of fluoxetine and desipramine in depressed women with advanced cancer.
      demonstrated that fluoxetine and desipramine were efficacious in relieving depression and improving quality of life for ambulatory cancer patients.
      In addition to their potential usefulness in treating depression, antidepressant medications have been used extensively as adjuvant treatments for cancer pain. Those antidepressants that impact multiple receptor systems, i.e., serotonergic, noradrenergic, and histaminic, may be the most useful in the treatment of pain.
      • Breitbart W
      Psychotropic adjuvant analgesics for cancer pain.
      Mirtazapine is an antidepressant that interacts with multiple neurotransmitter systems and multiple serotonergic receptor sites.
      • Nutt D
      Mirtazapine pharmacology in relation to adverse events.
      As a potent antagonist at the postsynaptic 5-HT2 and 5-HT3 serotonin receptor, mirtazapine may have potential as both an adjuvant analgesic and antiemetic.
      • Pederson L
      • Klysner R
      Antagonism of selective serotonin reuptake inhibitor-induced nausea by mirtazapine.
      As a potent blocker of the H1 receptor (histamine), mirtazapine also has potential as a sedative and appetite stimulant.
      • Richelson E
      Pharmacology of antidepressants-characteristics of the ideal drug.
      Insomnia and weight loss are two common and distressing symptoms for cancer patients,
      • Portenoy R
      • Thaler H
      • Kornblith A
      • et al.
      The Memorial Symptom Assessment Scale An instrument for the evaluation of symptom prevalence, characteristics, and distress.
      and this, therefore, may be an attractive aspect of mirtazapine therapy.
      Mirtazapine's potential to positively impact multiple symptoms in cancer patients, including pain, nausea, depression, insomnia, anxiety, and weight loss, make it an attractive medication for symptom management. In this pilot study, we sought to examine the impact of mirtazapine for multiply symptomatic cancer patients, selected initially for reports of residual pain despite being maintained on an opioid medication. We hypothesized that mirtazapine therapy would lead to improvements in pain, sleep, appetite, and depression over the patients' baseline. Effects on self-report measures of related symptoms and overall quality of life were explored. We chose this crossover, open-label design looking for a suggestion of efficacy prior to a randomized, double-blind trial. A crossover between 15 and 30 mg was conducted because of the unusual experience we, and others, have had with mirtazapine being more sedating and causing more weight gain at the lower dose. We wanted to investigate the possible benefits and drawbacks of this phenomenon, especially as it impacted the tolerability of the starting dose.

      Methods

      Procedures

      Twenty cancer patients who were experiencing visceral, somatic, or neuropathic pain and were on opioid medication were recruited and completed participation in this study. Patients either had to have scored a 3 or higher on a numeric rating scale with 0 being no pain whatsoever and 10 being the worst pain imaginable, or be maintained on opioid medications. Moderate to severe pain was used as a marker for more advanced disease and thus created the expectation that patients were polysymptomatic and therefore suitable for mirtazapine therapy. In addition, projected life expectancy for the subjects had to be 3 months or longer.
      Following a baseline assessment, patients completed a one-week observation period (study Week 1) and were then randomized to a starting dose of either 15 mg or 30 mg of mirtazapine given at bedtime. After three weeks (study Week 4), subjects were switched to the alternate dose and followed by an additional three-week period, completing the treatment (study Week 7). Patients were excluded from consideration if they were on antidepressant medication or if they were receiving corticosteroids, benzodiazepines, neuroleptics, or serotonin 5HT3 receptor antagonists for nausea or other symptoms.

      Measures

      Demographics

      A standard demographic questionnaire was employed in the study, including data on age, sex, race, marital status, educational level, and disease and treatment-related variables.

      Zung Self-Rating Depression Scale (ZSDS)

      The Zung Self-Rating Depression Scale (ZSDS)
      • Zung W
      Depression in the normal aged.
      • Zung W
      Factors influencing the self-rating depression scale.
      is a 20-item self-report measure of the symptoms of depression. Subjects rate each item regarding how they felt during the preceding week using a 4-point Likert scale. Scores are not meant to offer strict diagnostic guidelines but rather to denote levels of depressive symptomatology that may be of clinical significance. Overall, the ZSDS has been shown to be valid and to have high internal consistency, exhibiting an alpha coefficient of 0.84.
      • Dugan W
      • McDonald M
      • Passik S
      • et al.
      Use of the zung self-rating depression scale in cancer patients Feasibility as a screening tool.
      • Tate D
      • Forchheimer M
      • Maynard F
      • et al.
      Comparing two measures of depression in spinal cord injury.

      Functional Assessment of Cancer Therapy—General (FACT-G)

      The FACT-G is a 27-item self-administered questionnaire covering the quality of life domains of physical, social and family, emotional and functional well being. Items are rated on a 5-point Likert scale, from 0 (not at all) to 4 (very much) for how true each statement has been for the patient in the past seven days. The instrument is easy to use, brief, reliable, and valid. Currently in the fourth version, the measure has been deemed to be appropriate for use with all cancer patients.
      • Cella D
      • Bonomi A
      • Lloyd S
      • et al.
      Reliability and validity of the functional assessment of cancer therapy-lung (FACT-L) quality of life instrument.
      • Cella D
      • Tulsky D
      • Gray G
      • et al.
      The functional assessment of cancer therapy scale Development and validation.
      • Brady M
      • Cella D
      • Mo F
      • et al.
      Reliability and validity of the functional assessment of cancer therapy breast quality of life instrument.

      Memorial Pain Assessment Card (MPAC)

      The Memorial Pain Assessment Card (MPAC) consists of three visual analog scales used to measure pain intensity, pain relief and mood. In addition, it has one item in which the subject must choose from a list of eight descriptive words for pain.
      • Fishman B
      • Pastermak S
      • Wallenstein S
      • et al.
      The memorial pain assessment card a valid instrument for the assessment of cancer pain.

      Numeric Rating Scales (NRS)

      The NRS consisted of four questions covering nausea, anxiety, insomnia, and appetite. Patients were asked to circle the number that best described the symptom at its worst during a one-week period. The items utilized a 0–10 scale, with 0 meaning no presence of the symptom and 10 meaning that the symptom was as bad as could be imagined.

      Statistical Analyses

      Statistical analyses were conducted using the ZSDS, FACT-G, MPAC, and NRS in addition to several demographic variables. A series of descriptive statistics and Pearson Correlations were calculated. In addition, a series of repeated measures ANOVAs were conducted to compare the subjects' condition over time.

      Results

      A total of 36 subjects entered the study. Twenty subjects completed and were included in the analyses. There were a variety of reasons that the remaining 16 failed to complete the study. The sample was a mixed rural-urban sample of advanced cancer patients with significant pain being treated across Indiana. Seven patients died or became too ill to continue the study—this is a typical attrition rate for a study of this duration in our patient population. Six patients were being seen in the rural outreach clinics and were hospitalized; the primary care physician stopped the mirtazapine for unclear reasons. Those patients who missed medication for at least two days were excluded from the study. Two patients were lost to follow up to the cancer treatment center providing their care. Only one patient (30 mg dose of mirtazapine) withdrew from the study because of sedation caused by the mirtazapine.

      Demographics

      The sample of subjects completing the study comprised 13 men and 7 women. Demographic characteristics are summarized in Table 1. The primary cancer sites varied, with breast cancer (25%, n = 5), lung cancer (15%, n = 3), and lymphoma (15%, n = 3) being most common. There were no statistically significant correlations between the demographic variables and any of the assessment instruments, at any of the assessment points.
      Table 1Demographics of the Study Sample (n = 20)
      CharacteristicPercentageFrequency
      Sex
      Male65.0013
      Female35.007
      Marital Status
      Married90.0018
      Divorced5.001
      Widowed5.001
      Race
      Caucasian90.0018
      African-American10.002
      Education
      Grade 1–85.301
      Grade 8–1110.502
      High School Graduate42.108
      Some College (No Degree)21.04
      College Degree (BA or BS)5.301
      Some Post-College10.502
      Advanced Degree5.301
      Current Employment
      Disabled10.002
      Full Time25.005
      Part Time10.002
      Homemaker5.001
      Retired50.0010
      Mean (SD)Range
      Age60.15 (11.28)40–83
      The group of 16 drop-outs included 9 women and 7 men. To assess the generalizability of the results, a series of Chi-square analyses and independent samples t-tests were performed to compare the subjects who completed the study to the drop-out group. Chi-square analyses showed that the groups failed to significantly differ on gender (χ2 = 1.63, P = 0.20), marital status (χ2 = 5.29, P = 0.15), ethnicity (χ2= 0.17, P = 0.68), education level (χ2 = 3.41, P = 0.76), employment status (χ2 = 3.05, P = 0.55), or tumor type (χ2 = 9.76, P = 0.28). In addition, the independent samples t-tests failed to show any significant differences between these two groups based on age (t = 0.26, P = 0.61), ZSDS score (t = 0.08, P = 0.78), or FACT-G score (t = 0.96, P = 0.33).

      Pain and Other Symptoms

      A series of repeated measures ANOVAs showed no significant differences for either the MPAC items on pain, pain relief, and mood or the NRS scales measuring nausea, anxiety, insomnia, and appetite. However, responses to all of the items were in the hypothesized direction. For instance, mean responses decreased from baseline to study end for the MPAC item on pain intensity (mean = 3.7 to mean = 3.1) (F = 0.16, P = 0.70). This trend was also found by corresponding increasing scores in the MPAC relief question (mean = 6.8 to mean = 7.4) (F = 1.3, P = 0.28) and the MPAC mood question (mean = 7.0 to mean = 7.9) (F = 3.3, P = 0.10), again suggesting pain relief and mood benefit. The NRS scales for nausea (mean = 2.4 to mean = 0.9) (F = 3.4, P = 0.10), anxiety (mean = 2.7 to mean = 2.1) (F = 4.3, P = 0.07), insomnia (mean = 3.4 to mean = 2.3) (F = 1.5, P = 0.25), and appetite (mean = 3.9 to mean = 3.2) (F = 4.6, P = 0.10) all suggested a trend toward improvement from baseline to Week 7.

      Depression and Quality of Life

      At the baseline assessment, the mean ZSDS raw score was 40 (SD = 8.8) indicating mild depressive symptoms. A series of repeated measures ANOVAs were conducted using simple contrasts to compare the patients' status at week one, four, and seven to baseline while accounting for the crossover condition on dosages. Overall ZSDS scores were found to be significantly improved (F = 8.2, P < 0.05) at the end of the study (Week 7) and were not dependent on mirtazapine dosage. In addition to the overall scale, several analyses were conducted using the four factors identified in prior research
      • Passik S.D
      • Lundberg J.L
      • Rosenfeld B
      • et al.
      Factor analysis of the Zung self-rating depression scale in a large ambulatory oncology sample.
      and two single items from the ZSDS. Factor I (Cognitive symptoms) was not found to significantly differ when comparing either Week 4 (F = 0.002, P = 0.97) or week 7 (F = 2.3, P = 0.15) to baseline, although the results moved in the hypothesized direction. Similarly, Factor II (Manifest Depressed Mood) moved in the hypothesized direction, but was not found to be significant at either Week 4 (F = 1.1, P = 0.31) or Week 7 (F = 0.94, P = 0.35) compared to baseline. Factor III (Somatic Complaints: Non-eating Related) was not significantly improved at Week 4 (F = 3.4, P = 0.08) but was significantly improved at Week 7 (F = 9.0, P < 0.01). Factor IV (Somatic Complaints: Eating Related) was significantly improved at both Week 4 (F = 8.2, P < 0.05) and week 7 (F = 6.4, P < 0.05) compared to baseline. The single Zung item measuring appetite (“I eat as much as I used to”) exhibited significant improvement at Week 7 compared to baseline (F = 6.9, P < 0.05). Finally, the Zung item for weight (“I notice that I am losing weight”) indicated significantly less problem with weight loss at both Week 4 (F = 12.9, P < 0.01) and Week 7 (F = 4.7, P < 0.05) compared to baseline.
      Quality of life scores, as measured by the FACT-G, were significantly improved (F = 5.7, P < 0.05) at Week 7 and were not influenced by dosage condition. Comparable to the results on the ZSDS item mentioned above, patients' weights were significantly higher at both Week 4 (F = 8.7, P < 0.05) and Week 7 (F = 6.9, P < 0.05) and were again independent of dosage. Average weight gain from baseline to Week 4 was 2.6 pounds (mean increase from 162.8, SD = 32.2 to 165.5, SD = 30.12) and average weight gain from baseline to Week 7 was 2.0 pounds (mean increase 162.8, SD = 32.2 to 164.9, SD = 33.2).

      Discussion

      This pilot study suggests that mirtazapine may offer cancer patients with pain and multiple symptoms a variety of benefits. The main results suggest that cancer pain patients with mild symptoms of depression benefit over baseline with mirtazapine treatment at both 15 mg and 30 mg doses. Only one patient withdrew specifically because of mirtazapine side effects. There was no indication that there were issues related to the tolerability of the starting dose of mirtazapine (15 or 30 mg), though based on the sample size it is difficult to make a definite conclusion. Derogatis et al.
      • Derogatis L.R
      • Morrow G.R
      • Fetting J
      • et al.
      The prevalence of psychiatric disorders among cancer patients.
      suggested that cancer patients with pain are twice as likely as not to manifest a psychiatric disorder—principally adjustment disorder with depressed/anxious mood and major depression. Patients treated with mirtazapine in this study were all noticed to have improvement in depression scores at the end of 6 weeks of treatment (study Week 7) and this benefit was significantly correlated with an improvement in overall quality of life when compared to baseline.
      Change in ZSDS factor scores over time offer some interesting clues about how symptoms improve while taking mirtazapine. Factor IV (Somatic Complaints: Eating Related) was significantly improved early at week four and remained improved throughout the study period. Eating related symptoms were the first to improve. Factor III (Somatic Complaints: Non-eating related) improved only at Week 7, indicating that other physical complaints improved later. Factors I and II (Cognitive Symptoms and Manifest Depressed Mood), although indicating a beneficial trend, did not change significantly during the study period, suggesting that these more cognitive symptoms may be the last to respond to treatment or that they may be more resistant to change in this population, as can be the case with physically healthy patients. Nevertheless, improvements occur in quality of life based on other factors.
      Further work with mirtazapine is warranted in blinded trials and in comparison with other antidepressants with known benefit to cancer patients (i.e., fluoxetine)
      • Holland J.C
      • Romano S.J
      • Heiligenstein J.H
      • et al.
      A controlled trial of fluoxetine and desipramine in depressed women with advanced cancer.
      to assess relative benefits and tolerability. Mirtazapine treatment is potentially an example of the “side effect mobilization” approach to selecting adjuvant antidepressants for cancer patients. Advanced cancer patients, with multiple symptoms, may be candidates for such an approach. Certainly, many early stage cancer patients do not welcome weight gain or sedation, nor do they require that their antidepressant be anti-emetic. The serotonin-selective uptake inhibitors (SSRIs), stimulants and tertiary amine tricyclics provide a wide array of choices for these patients. However, for patients requiring drugs with mirtazapine's other benefits, the only choice historically open for them were the older tricyclic antidepressants (TCAs). While TCAs can help with sleep, appetite, and pain, they are difficult for advanced cancer patients to tolerate in doses relevant for treatment of depression because of anticholinergic side effects.

      Pain and Other Distressing Symptoms

      Improvement, though not statistically significant, was noted in multiple symptoms at the end of six weeks of mirtazapine therapy. These symptoms included pain, nausea, appetite, insomnia and anxiety. These differences are modest, though many patients, left untreated for six weeks, might very well have been expected to worsen with regard to these symptoms and overall quality of life. Indeed, weight gain in advanced cancer patients is certainly welcome and suggests that patients were indeed improving their intake. While it is impossible to know whether patients gained “good weight” (i.e., lean body mass) versus fluid or fat, it is interesting to note that none of the patients who gained weight had obvious signs of edema or ascites develop during the study. A randomized and/or placebo controlled trial (with a larger sample) might help to clarify these benefits and determine if they occur only in the presence of depression or if mirtazapine is independently a potential treatment for cachexia, nausea, and anxiety.

      Conclusion

      Mirtazapine therapy is probably beneficial to cancer patients in a number of ways. This pilot study suggests that mirtazapine may be effective for improving depression and quality of life, and may be effective for relieving multiple symptoms. Further research can help clarify the potential utility of this medication for the palliative care of cancer patients.
      • Yella S
      • Cella D
      • Webster K
      • et al.
      Measuring fatigue and other anemia-related symptoms with the functional assessment of cancer therapy (FACT-G) measurement system.
      ,
      • Winstead-Fry P
      • Schultz A
      Psychometric analysis of the functional assessment of cancer therapy-general (FACT-G) scale in a rural sample.

      Acknowledgements

      This study was supported by Organon Inc.

      References

        • Derogatis L.R
        • Morrow G.R
        • Fetting J
        • et al.
        The prevalence of psychiatric disorders among cancer patients.
        JAMA. 1983; 249: 751-757
        • Wells K.B
        • Stewart A
        • Hayes R.D
        • et al.
        The Functioning and Well-being of Depressed Patients.
        JAMA. 1989; 262: 914-919
        • Simon J
        • Glazer W
        Carving in and Keeping Mental Health Care in the Managed Care Setting.
        Psychiatric Services. 1995; 46: 1119-1120
        • Portenoy R
        • Thaler H
        • Kornblith A
        • et al.
        The Memorial Symptom Assessment Scale.
        Eur J Cancer. 1994; 30A: 1326-1336
        • Holland J.C
        • Romano S.J
        • Heiligenstein J.H
        • et al.
        A controlled trial of fluoxetine and desipramine in depressed women with advanced cancer.
        Psycho-Oncology. 1998; 7: 291-300
      1. Passik SD, Theobald DE, Lundberg J, et al. Initial results of an investigation of the effects of olanzapine for the relief of opioid-induced nausea in cancer pain patients, Midwest Pain Society 23rd Scientific Meeting, March 12–13, 1999, Chicago, IL.

      2. Passik SD, Theobald DE, Lundberg J, Donaghy K, Holtsclaw E, Kirsh K. The initial experiences with anti-depressant algorithm in a community based oncology clinic. Pan American Congress of Psychosocial and Behavioral Oncology, October 20–23, 1999, New York, NY.

        • Breitbart W
        Psychotropic adjuvant analgesics for cancer pain.
        Psycho-oncology. 1992; 1: 133-145
        • Nutt D
        Mirtazapine.
        Acta Psychiatrica Scandinavia. 1997; 96: 31-37
        • Pederson L
        • Klysner R
        Antagonism of selective serotonin reuptake inhibitor-induced nausea by mirtazapine.
        Int Clin Psychopharmacol. 1997; 12: 59-60
        • Richelson E
        Pharmacology of antidepressants-characteristics.
        Mayo Clin Proc. 1994; 69: 1069-1081
        • Zung W
        Depression in the normal aged.
        Psychosomatics. 1967; 7: 287-292
        • Zung W
        Factors influencing the self-rating depression scale.
        Arch Gen Psych. 1967; 16: 543-547
        • Dugan W
        • McDonald M
        • Passik S
        • et al.
        Use of the zung self-rating depression scale in cancer patients.
        Psycho-Oncology. 1998; 7: 483-493
        • Tate D
        • Forchheimer M
        • Maynard F
        • et al.
        Comparing two measures of depression in spinal cord injury.
        Rehabilitation Psychology. 1993; 38: 53-61
        • Cella D
        • Bonomi A
        • Lloyd S
        • et al.
        Reliability and validity of the functional assessment of cancer therapy-lung (FACT-L) quality of life instrument.
        Lung Cancer. 1995; 12: 199-220
        • Cella D
        • Tulsky D
        • Gray G
        • et al.
        The functional assessment of cancer therapy scale.
        J Clin Oncology. 1993; 11: 570-579
        • Brady M
        • Cella D
        • Mo F
        • et al.
        Reliability and validity of the functional assessment of cancer therapy breast quality of life instrument.
        J Clin Oncology. 1997; 15: 974-986
        • Yella S
        • Cella D
        • Webster K
        • et al.
        Measuring fatigue and other anemia-related symptoms with the functional assessment of cancer therapy (FACT-G) measurement system.
        J Pain and Symptom Manage. 1997; 13: 63-74
        • Winstead-Fry P
        • Schultz A
        Psychometric analysis of the functional assessment of cancer therapy-general (FACT-G) scale in a rural sample.
        Cancer. 1997; 79: 2446-2452
        • Fishman B
        • Pastermak S
        • Wallenstein S
        • et al.
        The memorial pain assessment card.
        Cancer. 1987; 60: 1151-1157
        • Passik S.D
        • Lundberg J.L
        • Rosenfeld B
        • et al.
        Factor analysis of the Zung self-rating depression scale in a large ambulatory oncology sample.
        Psychosomatics. 2000; 41: 121-127