APOS Clinical E-Mail Update #10
28 July 2004

In this Update:

What are the psychiatric side effects of thalidomide?

Kumar S, Witzig TE, Rajkumar SV.  Thalidomide: current role in the treatment of non-plasma cell malignancies.  J Clin Oncol 2004;22: 2477-2488.

Thalidomide is now in the anti-cancer armamentarium, a drug used widely in the treatment of multiple myeloma.  It is a drug that gained a reputation as an anti-angiogenic medication, but its mechanism of action is unclear.  This article reviews its role in tumors other than myeloma, particularly Kaposiís sarcoma and myelofibrosis.  It is likely to be a component of a variety of other tumor regimens.

From the perspective of the patientís mental health, thalidomide frequently causes drowsiness, somnolence, and constipation.  Skin rash is common.  It can contribute to orthostatic hypotension and dizziness.  Longer use fosters peripheral neuropathy.  Side effects that are less common include headache, confusion, malaise, asthenia, tremor, pruritus, impotence, loss of libido, nausea, and hypothyroidism.  Many side effects can be controlled with dose reduction; the well tolerated dose is less than 400 mg/day.

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Does yoga have a benefit for sleep in lymphoma patients?

Cohen L, Warneke C, Fouladi RT, Rodriguez MA, Chaoul-Reich A.  Psychological adjustment and sleep quality in a randomized trial of the effects of a Tibetan yoga intervention in patients with lymphoma.  Cancer 2004;100:2253-60.

Tibetan yoga, the practices of Tsa lung and Trul khor, incorporate controlled breathing and visualization, mindfulness techniques, and low-impact postures.  At MD Anderson, in a center for the clinical delivery of complementary programs, these researchers applied these techniques to 20 patients with lymphoma who were undergoing cancer treatment (typically CHOP-cyclophosphamide, doxorubicin, vincristine, and prednisone) or who had finished treatment in the last year.  These patients were compared to 19 other patients placed on a wait-list.  Most patients had 2 to 3 yoga sessions and 58% had at least 5 out of a planned 7 sessions.  Those who had yoga slept better than the control group on the wait list.  The measure of sleep quality was the Pittsburgh Sleep Quality Index.  Overall sleep disturbances, subjective sleep quality, sleep latency, sleep duraton, and use of sleep medications indicated better sleep in the yoga-treated group.  The study found that this kind of intervention was feasible in patients who were coping with lymphoma treatment.

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What is the course of recovery after hematopoietic cell transplantation?

Syrjala KL, Langer SL, Abrams JR, Storer B, Sanders JE, Flowers MED, Martin PJ.  Recovery and long-term function after hematopoietic cell transplantation for leukemia or lymphoma.  J Amer Med Assoc 2004;291:2335-2343.

This is a significant prospective, longitudinal cohort study of hematopoietic cell transplantation (HCT) patients at the Fred Hutchinson Cancer Research Center at the University of Washington School of Medicine in Seattle.  This study documents that full recovery after transplant takes 3 to 5 years.  The researchers followed 319 adults who had HCT for treatment of leukemia or lymphoma from before the procedure.  At 5 years, 99 long-term survivors remained, and 94 completed the assessment.  After one year, 21 patients (19%) had recovered in all realms; by 5 years 57 (63%) were without major limitations.  Greater depressive symptoms before the procedure was a characteristic of those with prolonged physical recovery.  After transplantation, those patients more depressed were more apt to have less social support before the procedure, to have graft-versus-host disease, and to be women.  Those who had more experience with cancer treatment before the procedure had more rapid recovery from depression and treatment-related distress.  They conclude that recovery might be faster with management of depression, improved social support, and interventions to improve the cabilities for work.  Physical recovery tends to occur before emotional recovery, but continuing physical complications are also related to higher rates of depression in later years.  Depression was measured by the Beck Depression Inventory and the Cancer Treatment Distress Scale.

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Would estrogen replacement reduce risk of dementia?

Shumaker SA, Legault C, Kuller L, Rapp SR, Thal L, et al.  Conjugated equine estrogens and incidence of proable dementia and mild cognitive impairment in postmenopausal women (Womenís Health Initiative Memory Study).  J Amer Med Assoc 2004;291:2947-2958.

Many patients with breast cancer, who had been deprived of estrogen treatment, particularly as their peers were treated with hormone replacement treatment, wondered whether they were missing a treatment that could maintain their ability to think.  With few options for treatment of dementia, estrogen was sometimes given as a treatment for dementia.  This is data from the Womenís Health Initiative a study of about 7500 women age 65-79, assessed from 1995-2002 or 2004.  About 3000 were taking estrogen alone, and about 4500 were taking estrogen and a progestin.  The overall hazard ratio for developing dementia or minimal cognitive dysfunction was greater for those who took estrogen alone or estrogen in combination with a progestin.  The hazard ratio was 1.76 for probable dementia in the estrogen alone group and 2.19 in the pooled trials.  Overall, estrogen therarpy did not reduce rates of dementia or minimal cognitive impairment in women 65 to 79 years old.

This result stands in counterpoint to the literature that suggests exogenous estrogen helps to protect cognitive function or to improve verbal memory.  It is still possible that estrogen replacement is helpful only during a crucial period, for instance, 3-10 months after ovariectomy, as shown in an animal model.  The authors conclude that neither conjugated equine estrogen nor combined treatment should not be initiated in older women to protect their cognitive function.  Those with low baseline cognitive function were at greater risk for the adverse hormonal effects on cognition.

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Correspondence on the interaction of tamoxifen and paroxetine

Ratliff B, Dietze EC, Bean GR, Moore C, Wanko S, Seewaldt, VL.  Re: Active tamoxifen metabolite plasma concentrations after co-administration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine.  J Natl Cancer Inst 2004;96; 883.

As reported in a previous Clinical Update, Stearns et al (1) had shown that the combination of tamoxifen and paroxetine led to a change in the tamoxifen metabolites such that endoxifen was increased.  These researchers, who wrote a letter to the editor of the J Natl Cancer Inst have shown that the cytotoxic pathway of tamoxifen that leads to apoptosis is independent of the cyctostatic, classic anti-estrogen action.  By looking at the serum concentrations of tamoxifen and its metabolites in the study and the affinity of the metabolites for the estrogen receptor, they conclude that a decrease in endoxifen would not substantially affect estrogen receptor function.  Furthermore, we do not know the role of endoxifen in treatment.  They conclude that paroxetine or other SSRIs should not be discontinued in patients receiving tamoxifen.

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Correspondence on the interaction of tamoxifen and paroxetine 2

Ponzone R, Biglia N, Sismondi P.  Re: Active tamoxifen metabolite plasma concentrations after co-administration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine.  J National Cancer Instit 2004;96:883-4.

In reference to the article about tamoxifen and paroxetine interaction, these correspondents also point out that the minimal active dose of tamoxifen is unknown.  There are no data on the efficacy of doses lower than 20 mg/day.  Marked dose reduction does not affect the concentration of insulin-like growth factor 1, for instance.  They note that the data reported by Stearns et al.1 are important, but not sufficient to prevent patients from taking drugs that improve the quality of their life.

1.  Stearns V, Johnson MD, Rae JM, Morocho A, Noviellie A, Bhargava P, et al.  active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the the selective seotonin reuptake inhibitor paroxetine.  J Natl Cancer Inst 2003;95:1758-64.

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Does anemia during chemotherapy affect both fatigue and decreased cognitive function?

Jacobsen PB, Garland LL, Booth-Jones M, Donovan KA et al.  Relationship of hemoglobin levels to fatigue and cognitive functioning among cancer patients receiving chemotherapy.  J Pain symptom Manage 2004;28:7-18.

Cancer patients receiving chemotherapy complain both of fatigue and cognitive difficulties.  These researchers at Moffit Cancer Center in Tampa, Florida, looked at the contribution of anemia to these two symptoms for the cancer patient in the midst of treatment.  They assessed 77 patients with a battery of cognitive performance tasks, a self-report fatigue measure, and the hemoglobin level.  Cancer patients with hemoglobin values less than 12 are known to have poorer quality of life and greater fatigue, so patients with hemoglobin less than 12 were evaluated separately.  Those 77 patients who completed both baseline and follow-up assessments included 49 with hemoglobin less than 12.  These were subjects with cancer, scheduled to have 4 cycles of chemotherapy, but those with a brain tumor or cranial radiation treatment were excluded.  The baseline assessment preceded chemotherapy, and the second evaluation came just before the fourth chemotherapy treatment.  The measure of fatigue was the Fatigue Symptom Inventory, and the cognitive assessment included the digit span subtest of the WAIS-III, the Hopkins Verbal learning test, the visual reproduction subtest of the WAIS-III, the Trail Making Test, the controlled oral word association test from the multilingual aphasia examination, and the National Adult Reading Test.  Those patients with hemoglobin less than 12 g/dL, were tired longer and more disrupted by the fatigue.  They also had more negative changes in performance on three cognitive tasks.  The authors concluded that drops in hemoglobin during chemotherapy mediate not only fatigue but decrements in cognitive function.

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Where is the evidence for pain, depression, and fatigue treatment in cancer patients?

The National Institute of Health State-of-the-Science Conference on Symptom Management in Cancer: Pain, Depression, and Fatigue.  J Natl Cancer Instit.  Monograph 2004:#32.

The monograph of the 2002 State of the Science Conference on symptomatic care of cancer patients has just been published.  It documents the literature on pain, fatigue, and depression in cancer patients and therefore provides an excellent bibliographic resource for anyone interested in the evidence.  Tools for assessment, known prevalence, and data for treatment are described as well as the barriers to care.  A non-advocate, non-Federal, 14 member panel of experts from medical oncology, geriatrics, pharmacology, psychology, neurology and psychology, nursing, public health, social work, and epidemiology heard the report.  The panel concluded that clinicians should ask about these symptoms, use brief assessment tools, and institute evidence based treatments.  They agreed that treatments are incompletely effective, that sufficient knowledge is lacking, and that patients often are reluctant to report their symptoms thinking that they must come with the cancer.  Reimbursement and coverage for these treatments are inadequate.  The panel supported adequately funded prospective studies.  This monograph should provide background information for many research proposals.

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Do patients who respond to placebo really experience less pain?

Wager TD, Rilling JK, Smith EE, Sokolik A, Casey KL et al.  Placebo-induced changes in fMRI in the anticipation and experience of pain.  Science 2004; 303:1162-1167.

Effective healers know that they must arouse hope in vulnerable patients.1  Patientsí reports of treatment response are influenced by the physicianís attention, interest, and concern for healing; the setting; the expectations of treatment; the reputations of the doctor; the expense; and the impressiveness of treatment.2  Stress amplifies the placebo effect.3

This paper focuses on placebo-induced analgesia, one aspect of the placebo response.  If the patient believes that pain will be relieved, that alone may reduce pain.  This reponse has been reversed by the opiate-antagonist naloxone.  These researchers hypothesize that placebo manipulations should reduce the experience of pain and that pain-responsive regions of the brain should show a reduced fMRI blood oxygen level-dependent signal during pain.  The thalamus, somatosensory cortex, insula, and anterior cingulated cortex make up the pain matrix.  Their second hypothesis is that placebo creates expectations for pain relief, which then inhibit activity in pain-processing regions.  This anticipation is related to prefrontal cortex and dorsolateral aspect of the frontal cortex modulation of internal representations.

Intense shock was compared to no shock in order to show physiological activation of the classic pain matrix.  The activation is ipsilateral in the cerebellum and contralateral in the ventrolateral prefrontal cortex, anterior cingulated, anterior insula, primary motor, secondary somatosensory, and thalamus.  Placebo treatment led to less pain than control conditions.  Only 8 of 24 participants showed a placebo effect.  The reduction in reported pain from control to placebo correlated with the magnitude of reduction of neural activity during the shock period.  The pattern is consistent with the concept of inhibition of afferent sensory pain transmission.

In order to test the second hypothesis, that the prefrontal cortex mediates placebo analgesia via expectation of pain relief, they examined the correlation between placebo effects and fMRI activity in the anticipation period.  They just looked at the dorsolateral prefrontal cortex and orbitofrontal cortex in relation to a thermal stimulus.  Activity in these areas correlated with the placebo response behaviorally and neurally.  This data supports a mechanism of placebo action modulated by activity in prefrontal cortex and expectations of pain.

All together, this study supports the notion that the placebo response reduces the experience of pain and not merely the report.  The data fit with the notion that prefrontal mechanisms trigger release of opioids in the midbrain.  The pain experience involves a cognitive and affective evaluation of the threat and the potential for relief.  This study highlights the benefit of placebo effects in those who anticipate relief.

1.  Frank JDD.  Persuasion and Healing.  New York:Schocken Books;1963.

2.  Straus JL, von Ammon, Cavanaugh S.  Placebo effects.  Issues for clinical practice in psychiatry and medicine.  Psychosomatics 1996;37:315-26.

3.  Beecher HK.  Evidence for increased effectiveness of placebos with increased stress.  Am J Physiol 1956;187:163-9.

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What works in family meetings during palliative care?

Chan, EKH, ONeill I, McKenzie M, Love A, Kissane DW.  What works for therapists conducting family meetings: treatment integrity in family-focused grief therapy during palliative care and bereavement.  J Pain Symp Manage 2004;27: 502-512.

Family focused grief therapy is a preventive intervention for families found to be at high risk for poor function during palliative care and bereavement.  This study assessed the therapistsí level of competence and their ability to adhere to the prescribed method of treatment.  The therapists who had formal training in family therapy included 2 psychiatrists and 15 social workers.  The 81 families were drawn from the community palliative care services at the University of Melbourneís Center for Palliative Care in Melbourne, Australia.  Patients had cancer, and this sample is taken from the treatment component of a randomized study.  Audio tapes were available for 69% of 285 sessions.  Key content-based domains coded in each phase of therapy included planning goals, understanding the familyís style, history, ideology, strengths, and key themes to address.  The core elements of the model were found in 86% therapistsí work.  These included exploration of the familyís cohesiveness, communication of thoughts and feelings, resolution of conflict.  The sessions were 90 minutes, 2 sessions of assessment; 4 to 6 meetings for intervention every 2 weeks or a month; and termination: one or two sessions at 2- to 3-month intervals.

Therapists were able to ask consistently about expectations of the family meetings, to clarify the purpose of the meeting, and to explore the familyís understanding of the illness, and to understand the familyís style and way of operating.  The task of identifying shared goals and formalizing a treatment plan were not done as often.  The therapists tried to understand the familyís history, to look for past patterns of rating, and to link these to the present.  These efforts could be documented more often than the task of eliciting prior patterns of expressing grief and loss.  The four main themes of the treatment—grief, communication, cohesiveness, and conflict—were reviewed consistently.

This paper documents a method to ensure the quality of a family therapy treatment, but its techniques may be useful for supervisors teaching novice therapists.  The therapists talked about loss, change, and grief in 78% of families.  Family communication was explored less as treatment went on; family conflict was explored later in treatment.  The therapists facilitated problem solving and assisted families with information, but the goal was a more comprehensive attention to family well-being.

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Are thoughts of hastening death common in hospice patients?

Arnold EM, Artin KA, Person JL, Griffith DL.  Consideration of hastening death among hospice patients and their families.  J Pain Symp Manage 2004;27:523-532.

This survey of 212 hospice social workers in the Southeast US brought 73 responses; of these, 41 social workers reported that a patient expressed the desire to hasten death, and 14 reported that a similar request came from a family member.  These requests had occurred an average of almost 3 times in the career of these social workers.  The patientís desire for death and family membersí request were linked to the patientís poor quality of life and concern for suffering, and the social workers attributed their condition in part to unmet needs, particularly less ability to participate in activities that make life enjoyable.  While the social workers, who are often sole mental health providers in the hospice setting, provided counseling and suicide prevention, they often felt that there were barriers to treatment, distrust of hospice staff or social isolation.  A little more than half of the patients were deemed depressed with a fear of being a burden.  Physical symptoms besides pain, loss of control over bodily function, and family conflict were also reasons for the wish to die, according to the social workers who responded.

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Can you describe the sleep abnormalities in breast cancer survivors with hot flashes?

Savard J, Davidson JR, Ivers H, Quesnel C, Rioux D, Dupere V, Lasnier M, Simard S, Morin CM.  The association between nocturnal hot flshes and sleep in breast cancer survivors.  J Pain Symptom Manage 2004;27:513-522.

Since breast cancer patients undergo chemotherapy that suppresses ovarian function or hastens menopause and since anti-estrogen treatments are added, hot flashes are a common occurrence following treatment.  This study documents in breast cancer survivors the sleep disturbance that correlates with hot flashes and the insomnia that often bother survivors in the first years after treatment.  With skin conductance and polysomnography, they recorded the sweating of hot flashes and the correlative change in sleep.  For 10 minutes around the flash, sleep was lighter and patients more awake than during times without flashes.  REM latency was longer, the percentage of Stage 2 sleep less. The 24 women in this study had just completed breast cancer treatment, had insomnia, and were not taking hormonal therapy. There was a mean of 2.7 hot flashes per woman in a 7-hour night. As other causes of insomnia are evaluated, particularly the insomnia of depression, it is worth noting that the sleep disruption of sudden estrogen deficiency has a distinct profile related to hot flashes.

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Donna B. Greenberg, MD, Associate Professor of Psychiatry at Harvard Medical School and Psychiatric Consultant in the Massachusetts General Hospital Cancer Center, Dana Farber Partners Cancer Care