APOS Clinical E-Mail Update #5
14 January 2004

In this Update:

Can you use chemotherapy in a patient on clozapine?

Rosenstock J. Clozapine therapy during cancer treatment. Am J Psychiatry 2004;161:175.

As a medication for schizophrenia, clozapine requires regular evaluation of the white count lest clozapine cause agranulocytosis. Rosenstock mentions five cases of patients who have taken clozapine in spite of cancer treatment and its additional risks of low white counts. He reports an additional case of a patient who developed persistent neutropenia even after cancer treatment ceased. She had adjuvant treatment for breast cancer with doxorubicin and cyclophosphamide, and following radiation treatment the white count continued below 3000 and neutrophil count below 2000. Other causes of neutropenia were excluded, so the persistent neutropenia may be related to a combination of clozapine and cancer treatment, but the patient has done well from a psychiatric and oncologic perspective.

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What does fluoxetine add for advanced cancer outpatients?

Fisch MJ, Loehrer PJ, Kristeller J, Passik S, Jung S-H, Jianzhao S, Arquette MA, Brames MJ, Einhorn LH. Fluoxetine versus placebo in advanced cancer outpatients: a double-blinded trial of the Hoosier Oncology Group J Clin Oncol 2003;21:1937-1943.

Two recent studies have evaluated the role of serotonin reuptake inhibitors in cancer treatment.1 Fisch et al. evaluated whether fluoxetine 20 mg for 12 weeks could improve the overall quality of life in outpatients with advanced cancer. These 163 patients, who were expected to survive only 3 to 24 months, were randomly given placebo or drug. The patients were asked first, whether they had often been bothered by feeling down, depressed, or hopeless during the past month; and secondly, whether they had been bothered by having little interest or pleasure in doing things. Of 129 patients who were evaluated, the patients treated with fluoxetine had a significant improvement in their score on the Functional Assessment of Cancer TherapyóGeneral (FACT-G) compared to placebo. The statistical technique was generalized estimating equation modeling. Although both the treatment and placebo group had similar depressive screening answers at baseline, the treated group had a lower level of depressive symptoms expressed. Those patients who reported more depressive symptoms on the two-question screen had the most benefit from fluoxetine. Women had significantly better outcomes. Those without a family history of depression had less depression. The treatment with fluoxetine as expected did not affect survival.

Daily headaches led two patients to drop out of the fluoxetine arm, and two stopped because of nausea and vomiting. One in the placebo group dropped out because of nausea and vomiting, and one for nonspecific side effects. The rate of vomiting was significantly greater in patients in the treatment arm at the last visit but no different at the second, third, and fourth visit.

The two-question screen here seems to identify a group of outpatients with advanced cancer who are more apt to respond to fluoxetine 20 mg with improved mood and quality of life.

1.  Morrow GR, Hickok JT, Roscoe JA, Raubrertas RF, Andrews PLR, Flynn PJ, Hynes HE, Banerjee TK, Kirshner JJ, King DK. Differential effects of paroxetine on fatigue and depression: a randomized, double-blind trial from the University of Rochester Cancer Center community clinical oncology program. J Clin Oncol 2003;21: 4635-4641

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Does paroxetine improve mood or fatigue in chemotherapy patients?

Morrow GR, Hickok JT, Roscoe JA, Raubrertas RF, Andrews PLR, Flynn PJ, Hynes HE, Banerjee TK, Kirshner JJ, King DK. Differential effects of paroxetine on fatigue and depression: a randomized, double-blind trial from the University of Rochester Cancer Center community clinical oncology program. J Clin Oncol 2003;21: 4635-4641.

This placebo-controlled study of community cancer patients who receive a serotonin-reuptake inhibitor antidepressant in the midst of chemotherapy adds to the literature by suggesting that patients as a group had fewer depressive symptoms and better overall mood at the end of chemotherapy if they were placed on paroxetine 20 mg. Distress, depressive symptoms, and fatigue are common during chemotherapy, and no formal assessment of the psychiatric diagnosis was made. In fact, patients with a history that suggested psychiatric diagnosis were excluded. This study offers some data for the common clinical conundrum of the oncology team. Should they add an antidepressant to the chemotherapy regimen to help with depression and anxiety even when the distress is difficult to sort from the toxicity of chemotherapy and the knowledge of the diagnosis?

This study drew from 704 community cancer patients scheduled to take four cycles of chemotherapy who reported fatigue during the week after their second chemotherapy cycle. Patients who were taking psychotropic medications or who had psychiatric history of mania, seizure, or psychiatric hospitalization were excluded. Paroxetine 20 mg or placebo were randomly provided for 8 weeks to 244 patients in the treatment group and 235 in the placebo group. Both fatigue and depression were assessed again at the week after cycles 3 and 4 of chemotherapy. The mean level of depression, determined by the Center for Epidemiologic Studies Depression (CES-D) scores were significantly lower in the group treated with paroxetine; the overall scores on the Profile of Mood States showed a benefit for mood. The majority of patients in this study had breast cancer (n=140), but patients with lung, hematological, gynecological, and gastrointestinal malignancies were also included. The mix of chemotherapy regimens was not described. The side effects of paroxetine were not described.

The drug treatment had no effect on fatigue ratings per se in either the depressed or non-depressed group when the fatigue one week after the second cycle of chemotherapy was compared to the fatigue after four cycles. Fatigue was measured by the Fatigue Symptom Checklist, the Monopolar Profile of Mood States (POMS) short form Fatigue/inertia subscale, and the Multidimensional Assessment of Fatigue. This outcome is not surprising since the fatigue incurred by catabolic chemotherapy treatments often increases from the second to the fourth cycle of chemotherapy, and there are likely many components to chemotherapy-related fatigue. The authors suggest that the ineffectiveness of paroxetine argues against a serotonin-mediated mechanism. Although fatigue has been one recognized feature of major depressive disorder, the patients with more severe depressive disorder have been excluded in the design. Paroxetine can reduce hot flashes that occur in the setting of breast cancer treatment and thereby improve sleep, but many patients may have not developed hot flashes at the time when four cycles of adjuvant treatment would have started.

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Do SSRIs and tamoxifen interact?

Stearns V, Johnson MD, Rae JM, Morocho A, Novielli A, Bhargava P, Hayes DF, Desta Z, Flockhart DA. Active tamoxifen metaoblite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J National Cancer Inst 2003;95:1758-64

Paroxetine has been used to alleviate hot flashes and to improve sleep and mood in breast cancer survivors taking tamoxifen. Stearns et al explored the interaction of these two drugs by measuring the metabolites of tamoxifen 20 mg before and after 4 weeks of paroxetine 10 mg per day. They found a new metabolite, endoxifen, 4-hydorxyl-N-desmethyl-tamoxifen; the level of endoxifen decreased significantly after paroxetine treatment. The endoxifen decreased by a greater proportion (64%) if the patient had a wild type CYP2D6 genotype compared to a variant CYP2D6 type. The metabolism of tamoxifen to endoxifen is first N-demthylation by cytochrome P 450 3A to N-desmethyl-tamoxifen by hydroxylation by cytochrome P450 2D6.

Endoxifen was as potent an inhibitor of estradiol in vitro as the other metabolite 4-hydroxy-tamoxifen. The authors acknowledge that they do not know the clinical implications of low circulating endoxifen concentrations and that this data should not alter treatment recommendations. It has been known that the levels of tamoxifen vary widely in patients on long-term adjuvant therapy for breast cancer, with a coefficient of variation of 50-70%.1

1.  Langan-Fahey SM. Tormey DC. Jordan VC. Tamoxifen metabolites in patients on long-term adjuvant therapy for breast cancer. European Journal of Cancer 1990;26:883-888.

Commenting on paroxetine and tamoxifen interaction:

Goetz MP, Loprinzi CL. A hot flash on tamoxifen metabolism. J National Cancer Inst 2003;95: 1734-5.

The editorial that accompanies the report of a tamoxifen-paroxetine interaction1 reviews the meaning of the finding. Goetz and Loprinzi note the benefit of paroxetine in promoting 60% reduction in hot flashes caused by tamoxifen compared to 20-30% with placebo. It remains unclear whether this change in metabolite level makes a clinical difference in the anti-cancer effect of tamoxifen.. Venlafaxine, which has also reduced hot flashes, causes less CYP2D6 inhibition than fluoxetine or paroxetine.

1.  Stearns V, Johnson MD, Rae JM, Morocho A, Novielli A, Bhargava P, Hayes DF, Desta Z, Flockhart DA. Active tamoxifen metaoblite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J National Cancer Inst 2003;95:1758-64.

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Is fatigue following breast cancer treatment based on inflammation?

Bower JE, Ganz PA, Aziz N, Fahey JL, Cole SW. T-cell homeostasis in breast cancer survivors with persistent fatigue. J National Cancer Institute 2003;95:1165-1168.

Perhaps the fatigue that follows breast cancer treatment is due to a chronic inflammatory process in the T-cell compartment. In order to explore a mechanism for the biological aspect of fatigue that follows breast cancer treatment, these researchers compared 20 fatigued breast cancer survivors (who had undergone surgery, radiation, and chemotherapy at least 2.5 years earlier) and 19 matched survivors who were not fatigued. They found significantly increased numbers of circulating T lymphocytes (31%) and CD56+ effector T lymphocytes (52%) in the fatigued survivors. The numbers of circulating T cells correlated with elevated levels of serum interleukin-1 receptor antagonists. The sample of fatigued survivors had a larger body mass, lower income, and more depressed mood than the control group. Bower et al hypothesize that subclinical immunological alterations underlie cancer-related fatigue syndromes.

These researchers had shown previously that fatigued patients even 5 years after diagnosis had significantly higher serum levels of interleukin-1 receptor antagonist (IL-1ra), soluble tumor necrosis factor receptor type II (sTNF-RII), and neopterin.1 Fatigued patients had lower levels of cortisol than the non-fatigued patients, and reported behavioral problems that co-occur with fatigue in the context of immune activation. Depressed mood was measured by the Beck Depression Inventory, and other items asked about the tendency to take naps, to feel like more rest than usual were needed, activity level, social interest, and cognitive difficulties.

1.  Bower JE, Ganz PA, Aziz N, Fahey JL. Fatigue and proinflammatory cytokine activity in breast cancer survivors. Psychosomatic Medicine 2002;64:604-611.

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How do you help cancer patients cope with fatigue?

Barsevick A, Whitmer K, Sweeney C, Nail LM. A pilot study examining energy conservation for cancer treatment-related fatigue. Cancer Nursing 2002;25:333-341.

These researchers piloted a nursing intervention for cancer-related fatigue. They assessed feasibility in 80 participants. They used a technique of energy conservation and activity management for one group undergoing active cancer treatment and but not the control group who also received cancer treatment. The intervention included three telephone sessions with an advanced nurse who focused on information about fatigue, development of an energy conservation plan, and evaluation of the planís effectiveness. Energy conservation includes activity pacing, priority setting with cognitive restructuring, active problem solving, patient/family education, and practiceórehearsal of target behaviors. The intervention was based on a common sense model in which information affected the cognitive representation of the symptom, personal guidance in formulating an energy conservation plan, and assistance in appraising the effectiveness of the effort. Participants completed homework that included a daily journal that monitored fatigue, sleep, rest, activity, and other symptoms. They made a list prioritizing their activities. In the second session, patients were assisted in making a plan for managing valued activity with a minimum of fatigue. In the third session, the plan was evaluated and revised. Patients, who received chemotherapy or radiation for a variety of solid tumors, participated in the sessions, said it was useful, and planned to continue the skills.

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Can neurocognitive measures added to tumor variables predict survival in lung cancer patients with brain metastases?

Meyers CA, Smith JA, Bezjak A, Mehta MP, Liebmann J, Illidge T, Kunkler I, Caudrelier H M, et al. Neurocognitive function and progression in patients with brain metastases treated with whole brain radiation and motexafin gadolinum: results of a randomized phase III trial. J Clin Oncol 2004;22:157-165.

Although this is a study of a specific technology, it is simply one of the first reports of prospective neurocognitive testing and analysis in a large sample of patients with brain metastases. It includes baseline pretreatment assessments of these patients impaired at baseline, often with multiple neurocognitive impairments. Not just tumor variables alone, but neurocognitive tests with the tumor variables seem to predict survival.

In lung cancer patients with brain metastases, memory and executive function improved and time to progressive neurocognitive dysfunction was delayed by motexafin gadolinium (MGd) added to whole brain radiation. More than 400 patients with brain metastases (251 with non-small cell lung cancer) were randomly assigned to receive whole brain radiation (30 Gy in 10 fractions with or without MGd). Brain tumor volume and survival were correlated with scores of memory, fine motor speed, executive function and global neurocognitive impairment. Survival was predicted by better pegboard dominant hand test scores, measures of motor speed and dexterity at baseline. More than two brain metastases, male sex, Karnofsky performance score, high LDH, low albumin, intermediate time from primary tumor diagnosis to enrollment and not breast cancer primary.

Lung cancer patients were distinct in this study as they more often present with brain metastases before the primary tumor, with smaller lesion volume, and less prior therapy. It may be easier to show a treatment benefit in this group.

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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