Gary R. Morrow

Recommendations for the Use of Antiemetics: Evidence-Based, Clinical Practice Guidelines

THE GOAL OF ANTIEMETIC therapy is to prevent nausea and vomiting completely. This goal is achieved for many patients receiving chemotherapy or radiation therapy, and is based on clinical and basic research that has steadily improved the control of emesis over the last 20 years. As therapy has become more effective, it has also become safer, with few side effects associated with the most commonly used regimens. These regimens are convenient for patients to receive and for health care professionals to administer. However, despite improvements, a significant number of patients still experience emesis, and efforts to reduce this side effect of treatment must continue. As antiemetic usage has grown, the classes of agents available for antiemetic treatment, the number of agents, and the indications for antiemetics have all increased as well. The prevention of delayed emesis and anticipatory emesis is equal in importance to the need to prevent acute chemotherapyand radiation-induced emesis. Additionally, managing special and difficult emetic problems and selecting the proper antiemetic approach necessitate identification of the patient’s emetic risk. Although the neuropharmacologic basis of emesis is still incompletely understood, the selection of an appropriate antiemetic regimen is possible and can have an impact on several aspects of clinical care. Goals related to the complete control of emesis, ie, no vomiting, include providing care that is convenient for the patient, treatment that reduces hospitalization and time in the ambulatory setting, and therapy that enhances the patient’s quality of life. Additionally, practitioners need to be mindful of reducing costs of treatment while achieving these goals. 1-3

Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update

PURPOSE To update the American Society of Clinical Oncology (ASCO) guideline for antiemetics in oncology. METHODS A systematic review of the medical literature was completed to inform this update. MEDLINE, the Cochrane Collaboration Library, and meeting materials from ASCO and the Multinational Association for Supportive Care in Cancer were all searched. Primary outcomes of interest were complete response and rates of any vomiting or nausea. RESULTS Thirty-seven trials met prespecified inclusion and exclusion criteria for this systematic review. Two systematic reviews from the Cochrane Collaboration were identified; one surveyed the pediatric literature. The other compared the relative efficacy of the 5-hydroxytryptamine-3 (5-HT(3)) receptor antagonists. RECOMMENDATIONS Combined anthracycline and cyclophosphamide regimens were reclassified as highly emetic. Patients who receive this combination or any highly emetic agents should receive a 5-HT(3) receptor antagonist, dexamethasone, and a neurokinin 1 (NK(1)) receptor antagonist. A large trial validated the equivalency of fosaprepitant, a single-day intravenous formulation, with aprepitant; either therapy is appropriate. Preferential use of palonosetron is recommended for moderate emetic risk regimens, combined with dexamethasone. For low-risk agents, patients can be offered dexamethasone before the first dose of chemotherapy. Patients undergoing high emetic risk radiation therapy should receive a 5-HT(3) receptor antagonist before each fraction and for 24 hours after treatment and may receive a 5-day course of dexamethasone during fractions 1 to 5. The Update Committee noted the importance of continued symptom monitoring throughout therapy. Clinicians underestimate the incidence of nausea, which is not as well controlled as emesis.

Differential Effects of Paroxetine on Fatigue and Depression: A Randomized, Double-Blind Trial From the University of Rochester Cancer Center Community Clinical Oncology Program

PURPOSE Fatigue and depression typically occur together in cancer patients, suggesting a common etiology, perhaps based on serotonin. This randomized clinical trial tested whether paroxetine, a selective serotonin reuptake inhibitor antidepressant known to modulate brain serotonin, would reduce fatigue in cancer patients and whether any reduction was related to depression. PATIENTS AND METHODS Cancer patients undergoing chemotherapy for the first time were assessed for fatigue. Of 704 patients who reported fatigue at their second chemotherapy cycle, 549 patients were randomly assigned to receive either 20 mg of oral paroxetine hydrochloride daily or placebo for 8 weeks. The assessments of fatigue and depression were performed at cycles 3 and 4 of chemotherapy. RESULTS A total of 244 patients treated with paroxetine and 235 patients treated with placebo provided assessable data. No difference was detected in fatigue between patient groups. At the end of the study, there was a difference between groups in the mean level of depression (Center for Epidemiologic Studies Depression scores, 12.0 v 14.8, respectively; P <.01). CONCLUSION Paroxetine had no influence on fatigue in patients receiving chemotherapy. A possible explanation is that cancer-related fatigue does not involve a reduction in brain 5-HT levels.

Prevalence, Demographics, and Psychological Associations of Sleep Disruption in Patients With Cancer: University of Rochester Cancer Center―Community Clinical Oncology Program

PURPOSE Sleep disruption is prevalent in patients with cancer and survivors, but the prevalence of insomnia, a distressing sleep disorder, in these populations has yet to be determined in large-scale studies. PATIENTS AND METHODS A total of 823 patients with cancer receiving chemotherapy (mean age, 58 years; 597 female patients) reported on sleep difficulties in a prospective study. RESULTS During day 7 of cycle 1 of chemotherapy, 36.6% (n = 301) of the patients with cancer reported insomnia symptoms, and 43% (n = 362) met the diagnostic criteria for insomnia syndrome. Patients with cancer younger than 58 years were significantly more likely to experience either symptoms of insomnia or insomnia syndrome (chi(2) = 13.6; P = .0002). Patients with breast cancer had the highest number of overall insomnia complaints. A significant positive association was found between symptoms of insomnia during cycles 1 and 2 of chemotherapy (phi = .62, P < .0001), showing persistence of insomnia during the first two cycles of chemotherapy. Sixty percent of the patient sample reported that their insomnia symptoms remained unchanged from cycle 1 to cycle 2. Those with insomnia complaints had significantly more depression and fatigue than good sleepers (all P < .0001). CONCLUSION The proportions of patients with cancer in this sample reporting symptoms of insomnia and meeting diagnostic criteria for insomnia syndrome during chemotherapy are approximately three times higher than the proportions reported in the general population. Insomnia complaints persist throughout the second chemotherapy cycle for the majority of patients with cancer in this study. Insomnia is prevalent, underrecognized, undermanaged, and understudied among patients with cancer receiving chemotherapy.

Gabapentin for hot flashes in 420 women with breast cancer: a randomised double-blind placebo-controlled trial

BACKGROUND Most women receiving systemic therapy for breast cancer experience hot flashes. We undertook a randomised, double-blind, placebo-controlled, multi-institutional trial to assess the efficacy of gabapentin in controlling hot flashes in women with breast cancer. METHODS 420 women with breast cancer who were having two or more hot flashes per day were randomly assigned placebo, gabapentin 300 mg/day, or gabapentin 900 mg/day by mouth in three divided doses for 8 weeks. Each patient kept a 1-week, self-report diary on the frequency, severity, and duration of hot flashes before the start of the study and during weeks 4 and 8 of treatment. Analyses were by intention to treat. FINDINGS Evaluable data were available on 371 participants at 4 weeks (119 placebo, 123 gabapentin 300 mg, and 129 gabapentin 900 mg) and 347 at 8 weeks (113 placebo, 114 gabapentin 300 mg, and 120 gabapentin 900 mg). The percentage decreases in hot-flash severity score between baseline and weeks 4 and 8, respectively were: 21% (95% CI 12 to 30) and 15% (1 to 29) in the placebo group; 33% (23 to 43) and 31% (16 to 46) in the group assigned gabapentin 300 mg; and 49% (42 to 56) and 46% (34 to 58) in the group assigned gabapentin 900 mg. The differences between the groups were significant (p=0.0001 at 4 weeks and p=0.007 at 8 weeks by ANCOVA for overall treatment effect, adjusted for baseline values); only the higher dose of gabapentin was associated with significant decreases in hot-flash frequency and severity. INTERPRETATION Gabapentin is effective in the control of hot flashes at a dose of 900 mg/day, but not at a dose of 300 mg/day. This drug should be considered for treatment of hot flashes in women with breast cancer.

Nausea and emesis remain significant problems of chemotherapy despite prophylaxis with 5-hydroxytryptamine-3 antiemetics: A University of Rochester James P. Wilmot cancer center community clinical oncology program study of 360 cancer patients treated in the community

Clinical reports suggest that nausea remains a side effect of chemotherapy despite widespread use of serotonin receptor antagonists. This study summarized the frequency, timing, and intensity of postchemotherapy nausea for patients receiving doxorubicin, cisplatin, or carboplatin.

Effect of paroxetine hydrochloride (Paxil®) on fatigue and depression in breast cancer patients receiving chemotherapy

SummaryBackground. Fatigue can significantly interfere with a cancer patient’s ability to fulfill daily responsibilities and enjoy life. It commonly co-exists with depression in patients undergoing chemotherapy, suggesting that administration of an antidepressant that alleviates symptoms of depression could also reduce fatigue. Methods. We report on a double-blind clinical trial of 94 female breast cancer patients receiving at least four cycles of chemotherapy randomly assigned to receive either 20 mg of the selective serotonin re-uptake inhibitor (SSRI) paroxetine (Paxil®, SmithKline Beecham Pharmaceuticals) or an identical-appearing placebo. Patients began their study medication seven days following their first on-study treatment and continued until seven days following their fourth on-study treatment. Seven days after each treatment, participants completed questionnaires measuring fatigue (Multidimensional Assessment of Fatigue, Profile of Mood States-Fatigue/Inertia subscale and Fatigue Symptom Checklist) and depression (Profile of Mood States-Depression subscale [POMS-DD] and Center for Epidemiologic Studies-Depression [CES-D]). Results. Repeated-measures ANOVAs, after controlling for baseline measures, showed that paroxetine was more effective than placebo in reducing depression during chemotherapy as measured by the CES-D (p=0.006) and the POMS-DD (p=0.07) but not in reducing fatigue (all measures, ps > 0.27). Conclusions. Although depression was significantly reduced in the 44 patients receiving paroxetine compared to the 50 patients receiving placebo, indicating that a biologically active dose was used, no significant differences between groups on any of the measures of fatigued were observed. Results suggest that modulation of serotonin may not be a primary mechanism of fatigue related to cancer treatment.

Group psychotherapy for recently diagnosed breast cancer patients: a multicenter feasibility study.

As many as 80% of breast cancer patients report significant distress during initial treatment, yet there is little in the way of systematic psychotherapeutic interventions for women coping with the stress of a recent diagnosis of breast cancer. The literature on psychotherapeutic treatment of cancer patients provides uniform evidence for an improvement in mood, coping and adjustment as a result of group therapy. The present study examined the feasibility of implementing a manualized treatment, supportive–expressive group psychotherapy, in busy oncology practices across the US. This intervention was applied to women with primary breast cancer in a manner which tests not only the efficacy of the approach but also its accessibility to group therapists not previously experienced in its use. One hundred and eleven breast cancer patients within 1 year of diagnosis were recruited from ten geographically diverse sites of the National Cancer Institutes Community Clinical Oncology Program (CCOP) and two academic medical centers. Two therapists from each site were trained in supportive–expressive group psychotherapy. Training consisted of participation in a workshop, reading a treatment manual, and viewing explanatory videotapes. Each patient participated in a supportive–expressive group that met for 12 weekly sessions lasting 90 min. Assessment of mood disturbance was made at entry, 3, 6, and 12 months. Results indicated a significant 40% decrease in the Total Mood Disturbance (TMD) scores of the Profile of Mood States (POMS) (ANOVA F [2,174]=3.98, p<0.05). The total symptom score of the Hospital Anxiety and Depression Scale (HADS) was likewise significantly reduced over the 6‐month period (F [2,174]=5.2, p<0.01). Similarly, the total score of the Impact of Event Scale (IES) was significantly reduced (F [2,174]=4.0, p<0.05). There was substantial uniformity of treatment effect across sites. Outcome was independent of stage of disease (I vs. II). We conclude that this treatment program can be effectively implemented in a community setting and results in reduced distress among breast cancer patients. Copyright

A randomized clinical trial of alprazolam versus progressive muscle relaxation in cancer patients with anxiety and depressive symptoms.

A randomized nonblinded study was performed in three cancer centers to test over a 10-day period the efficacy of (1) a triazolobenzodiazepine, alprazolam, 0.5 mg three times a day and (2) use of a behavioral technique in which patients were trained in progressive muscle relaxation at an initial session with a behavioral psychologist and then asked to listen at home to an audiotape of the session three times a day. Of 147 cancer patients who met entry levels of distress and completed the study, uncontrolled for site or disease stage, 70 were randomized to drug, 77 to relaxation. Four measures of anxiety and depression were used: Covi, Raskin, Affects Balance, and Symptoms Checklist-90 (SCL-90). Results showed that both treatment arms resulted in significant (P less than .001) decrease in observer and patient-reported anxious and depressed mood symptoms. Although both treatment arms were effective, patients receiving the drug showed a slightly more rapid decrease in anxiety and greater reduction of depressi...

Nausea and Vomiting Remain a Significant Clinical Problem: Trends Over Time in Controlling Chemotherapy-Induced Nausea and Vomiting in 1413 Patients Treated in Community Clinical Practices

Data from 1413 outpatients in community-based clinical practices were collected in order to characterize the use and effectiveness of 5-HT(3) receptor antagonists for control of chemotherapy-induced nausea and vomiting (NV). Patients were divided by treatment starting date into six cohorts for trend analysis. In addition, NV symptoms were compared in 252 patients treated prior to the commercial introduction of the 5-HT(3) receptor antagonist antiemetics, and an equal number of patients treated after their introduction. A comparison of cohorts revealed a significant (P = 0. 027) downward trend over time for the frequency of post-treatment vomiting episodes, but not for frequency of post-treatment nausea (P = 0.69). The average duration of nausea following treatment increased significantly over time (P = 0.003). Although the introduction of 5-HT(3) receptor antagonist antiemetics has apparently led to a significant reduction in the frequency of post-treatment vomiting, there has been an accompanying increase in the duration of post-treatment nausea.