Michele Y. Halyard

Phase III Evaluation of Fluoxetine for Treatment of Hot Flashes

PURPOSE Hot flashes can be a prominent problem in women with a history of breast cancer. Given concerns regarding the use of hormonal therapies in such patients, other nonhormonal means for treating hot flashes are required. Based on anecdotal information regarding the efficacy of fluoxetine and other newer antidepressants for treating hot flashes, the present trial was developed. PATIENTS AND METHODS This trial used a double-blinded, randomized, two-period (4 weeks per period), cross-over methodology to study the efficacy of fluoxetine (20 mg/d) for treating hot flashes in women with a history of breast cancer or a concern regarding the use of estrogen (because of breast cancer risk). Eligible patients had to have reported that they averaged at least 14 hot flashes per week; they could have received tamoxifen or raloxifene as long as they were on a stable dose. The major outcome measure was a bivariate construct representing hot flash frequency and hot flash score, analyzed by a classic sums and differences cross-over analysis. RESULTS Eighty-one randomized women began protocol therapy. By the end of the first treatment period, hot flash scores (frequency x average severity) decreased 50% in the fluoxetine arm versus 36% in the placebo arm. Cross-over analysis demonstrated a significantly greater marked hot flash score improvement with fluoxetine than placebo (P =.02). The results were not adjusted for potential confounding influences, including age and tamoxifen use. The fluoxetine was well tolerated. CONCLUSION This dose of fluoxetine resulted in a modest improvement in hot flashes.

The impact of measuring patient-reported outcomes in clinical practice: a systematic review of the literature

ObjectiveThe purpose of this paper is to summarize the best evidence regarding the impact of providing patient-reported outcomes (PRO) information to health care professionals in daily clinical practice.MethodsSystematic review of randomized clinical trials (Medline, Cochrane Library; reference lists of previous systematic reviews; and requests to authors and experts in the field).ResultsOut of 1,861 identified references published between 1978 and 2007, 34 articles corresponding to 28 original studies proved eligible. Most trials (19) were conducted in primary care settings performed in the USA (21) and assessed adult patients (25). Information provided to professionals included generic health status (10), mental health (14), and other (6). Most studies suffered from methodologic limitations, including analysis that did not correspond with the unit of allocation. In most trials, the impact of PRO was limited. Fifteen of 23 studies (65%) measuring process of care observed at least one significant result favoring the intervention, as did eight of 17 (47%) that measured outcomes of care.ConclusionsMethodological concerns limit the strength of inference regarding the impact of providing PRO information to clinicians. Results suggest great heterogeneity of impact; contexts and interventions that will yield important benefits remain to be clearly defined.

Implementing patient-reported outcomes assessment in clinical practice: a review of the options and considerations

PurposeWhile clinical care is frequently directed at making patients “feel better,” patients’ reports on their functioning and well-being (patient-reported outcomes [PROs]) are rarely collected in routine clinical practice. The International Society for Quality of Life Research (ISOQOL) has developed a User’s Guide for Implementing Patient-Reported Outcomes Assessment in Clinical Practice. This paper summarizes the key issues from the User’s Guide.MethodsUsing the literature, an ISOQOL team outlined considerations for using PROs in clinical practice; options for designing the intervention; and strengths, weaknesses, and resource requirements associated with each option.ResultsImplementing routine PRO assessment involves a number of methodological and practical decisions, including (1) identifying the goals for collecting PROs in clinical practice, (2) selecting the patients, setting, and timing of assessments, (3) determining which questionnaire(s) to use, (4) choosing a mode for administering and scoring the questionnaire, (5) designing processes for reporting results, (6) identifying aids to facilitate score interpretation, (7) developing strategies for responding to issues identified by the questionnaires, and (8) evaluating the impact of the PRO intervention on the practice.ConclusionsIntegrating PROs in clinical practice has the potential to enhance patient-centered care. The online version of the User’s Guide will be updated periodically.

The use of radiotherapy for patients with isolated elevation of serum prostate specific antigen following radical prostatectomy

PURPOSE An analysis was performed to assess the outcome of patients who received radiotherapy for isolated elevation of serum prostate specific antigen (PSA) levels following radical retropubic prostatectomy. MATERIALS AND METHODS Forty-six patients were initially treated for localized prostate cancer with radical retropubic prostatectomy following negative pelvic lymphadenectomy. These patients had detectable serum PSA 6 or more months postoperatively. No patient had other clinical evidence of recurrent disease as determined by history, physical examination, bone scan, computerized tomography of the abdomen and pelvis, chest radiographs, complete blood cell counts and serum chemistry profiles. The patients received prostate bed irradiation using 10 MV. x-rays and a 4-field approach. Doses ranged from 60.0 to 67.0 Gy. in 1.8 to 2.0 Gy. fractions. Freedom from failure after radiotherapy was defined as maintaining a PSA of 0.3 ng./ml. or less without hormonal intervention. RESULTS In 27 of the 46 patients (59%) PSA had decreased to 0.3 ng./ml. or less at last measurement without hormonal intervention. The freedom from failure rate was 50% at 3 and 5 years. More favorable responses to salvage radiotherapy occurred in patients with low grade tumors and serum PSA 1.1 ng./ml. or less at initiation of radiotherapy. Patients, receiving radiation doses of 64 Gy. or more had more favorable response rates than those receiving lesser doses. CONCLUSIONS Isolated elevations of serum PSA following prostatectomy reflect residual disease. Radiotherapy administered to the prostate bed effectively decreased serum PSA in approximately half of the cases. This effect appears to be accomplished by eradicating tumor cells in the prostate bed.

Radiotherapy and Adjuvant Trastuzumab in Operable Breast Cancer: Tolerability and Adverse Event Data From the NCCTG Phase III Trial N9831

PURPOSE To assess whether trastuzumab (H) with radiotherapy (RT) increases adverse events (AEs) after breast-conserving surgery or mastectomy. PATIENTS AND METHODS Patients with early-stage resected human epidermal growth factor receptor 2 (HER-2) -positive breast cancer (BC) were randomly assigned to doxorubicin (A) and cyclophosphamide (C), followed by weekly paclitaxel (T; AC-T-H or AC-TH-H). RT criteria (with or without nodal RT) were postlumpectomy breast or (optional) postmastectomy chest wall. RT of internal mammary nodes was prohibited. RT commenced within 5 weeks after T, concurrently with H. Analysis included 1,503 irradiated patients for RT-associated AEs across treatment arms. Rates of cardiac events (CEs) with and without RT were compared within arms. RESULTS No significant differences among arms were found in incidence of acute skin reaction, pneumonitis, dyspnea, cough, dysphagia, or neutropenia. A significant difference occurred in incidence of leukopenia, with higher rates for AC-T-H versus AC-T (odds ratio = 1.89; 95% CI, 1.25 to 2.88). At a median follow-up of 3.7 years (range, 0 to 6.5 years), RT with H did not increase relative frequency of CEs regardless of treatment side. The cumulative incidence of CEs with AC-T-H was 2.7% with or without RT. With AC-TH-H, the cumulative incidence was 1.7% v 5.9% with or without RT, respectively. CONCLUSION Concurrent adjuvant RT and H for early-stage BC was not associated with increased acute AEs. Further follow-up is required to assess late AEs.

I'm so tired: biological and genetic mechanisms of cancer-related fatigue

ObjectiveThe goal of this paper is to discuss cancer-related fatigue (CRF) and address issues related to the investigation into potential biological and genetic causal mechanisms. The objectives are to: (1) describe CRF as a component of quality of life (QOL); (2) address measurement issues that have slowed progress toward an understanding of mechanisms underlying this symptom; (3) review biological pathways and genetic approaches that have promise for the exploration of causal mechanisms of CRF; and (4) offer directions for future research.MethodsReview, synthesis, and interpretation of the literature.ResultsUntil recently, CRF and QOL have been understood primarily as subjective patient-reported experiences. With increased understanding of human genetics, theories and research are being expanded to incorporate biological and genetic understandings of these subjective experiences. Proposed biological and genetic mechanisms of CRF that have been examined include cytokine dysregulation, hypothalamic–pituitary–adrenal (HPA) axis dysfunction, five hydroxy tryptophan (5-HT) neurotransmitter dysregulation, circadian rhythm disruption, alterations in adenosine triphosphate (ATP) and muscle metabolism, and vagal afferent activation. Approaches to the study of genetic mechanisms have also been addressed including candidate genes, genome-wide scanning, and gene expression. Based on the review and synthesis of the literature, directions for future research are proposed.ConclusionsUnderstanding the biological and genetic basis of CRF has the potential to contribute to a more complete understanding of the genetic determinants of QOL.

Exploration of the Value of Health-Related Quality-of-Life Information From Clinical Research and Into Clinical Practice

Quality-of-life (QOL) instruments used in clinical research can provide important evidence to inform decisions about alternative treatments. This is particularly true when patients, such as those with cancer who are contemplating toxic chemotherapy, face tradeoffs between quantity of life and QOL or when the primary goal of therapy is to improve how patients feel. Surrogate measures (cardiac function, exercise capacity, bone density, tumor size) are inadequate substitutes for direct measurement of QOL. Quality-of-life measures will be most valuable when they comprehensively measure aspects of QOL that are both important to patients and likely to be influenced by therapy, when the QOL measurement instruments are valid (measuring what is intended) and responsive (able to detect all important changes, even if small), and when the results are readily interpretable (determining whether treatment-related changes are trivial, small but important, or large). Researchers are finding new, imaginative ways to help clinicians understand the magnitude of treatment impact on QOL. Additionally, QOL measures may be useful in clinical practice. Recent results from well-designed randomized controlled trials suggest that information on patient QOL provided to clinicians might, in some circumstances, result in benefits for these patients. Further investigation is warranted to confirm these observations and to define the particular combination of methods and settings most likely to yield important benefits.

Breast cancer-related lymphedema

Every year in the United States, breast cancer is diagnosed in more than 200,000 women. Because of the prevalence of breast cancer, treatment-related sequelae are of Importance to many survivors of the disease. One such sequela is upper extremity lymphedema, which occurs when fluid accumulates in the Interstitial space and causes enlargement and usually a feeling of heaviness in the limb. Axillary surgery contributes considerably to the incidence of lymphedema, with the incidence and severity of swelling related to the number of lymph nodes removed. Lymphedema after standard axillary lymph node dissection can occur in up to approximately 50% of patients. However, the risk of lymphedema is decreased substantially with newer sentinel lymph node sampling procedures. Adjuvant radiotherapy to the breast or lymph nodes increases the risk of lymphedema, which has been reported in 9% to 40% of these patients. Management of lymphedema requires a multidisciplinary approach to minimize the effect on the patients quality of life. This review presents an overview of the pathophysiology, diagnosis, prevention, and treatment of breast cancer-related lymphedema.

The results of radical retropubic prostatectomy and adjuvant therapy for pathologic Stage C prostate cancer

PURPOSE The results of therapy in 288 men with pathologic Stage C prostate cancer who underwent radical retropubic prostatectomy (RRP) were analyzed to determine the effects of adjuvant therapy. METHODS AND MATERIALS Twenty-seven of the 288 patients received preoperative neoadjuvant hormonal therapy (leuprolide acetate). Postoperatively, 60 patients received adjuvant radiotherapy (RT) to the prostate bed. Follow-up ranged from 3 to 83 months (median = 32 months). Freedom from failure (FFF) was defined as maintaining a serum PSA level of < or = 0.3 ng/ml. RESULTS The FFF was 61% at 3 years and 45% at 5 years for the entire group. The FFF following RRP plus RT was 75% at 3 years and 57% at 5 years as compared to 56% at 3 years and 40% at 5 years for RRP without RT (p=0.049). The FFF following RRP plus neoadjuvant hormonal therapy was 58% at 3 years and 40% at 5 years as compared to 60% at 3 years and 45% at 5 years following RRP without hormonal therapy (p=0.3). In patients without seminal vesicle (SV) invasion, the FFF was 81% at 3 years and 5 years for RRP plus RT as compared to 61% at 3 years and 50% at 5 years for RRP without RT (p=0.01). In patients with SV invasion, the FFF was 61% at 3 years and 36% at 5 years for RRP plus RT as compared to 44% at 3 years and 23% at 5 years for RRP without RT (p=0.23). The projected local control rate was 83% at 5 years for those with RRP alone as compared to 100% for RRP plus RT (p=0.02). Survival at 5 years was projected to be 92% and was not significantly altered by the administration of adjuvant therapies. CONCLUSIONS Postoperative RT was associated with significantly improved local control and FFF rates, especially in patients with tumors which did not involve the seminal vesicles.

Prognostic factors in Merkel cell carcinoma: Analysis of 240 cases

BACKGROUND Knowledge regarding behavior of and prognostic factors for Merkel cell carcinoma (MCC) is limited. OBJECTIVE We sought to further understand the characteristics, behavior, prognostic factors, and optimal treatment of MCC. METHODS A multicenter, retrospective, consecutive study of patients with known primary MCC was completed. Overall survival and survival free of locoregional recurrence were calculated and statistical analysis of characteristics and outcomes was performed. RESULTS Among the 240 patients, the mean age at diagnosis was 70.1 years, 168 (70.0%) were male, and the majority was Caucasian. The most common location was head and neck (111, 46.3%). Immunosuppressed patients had significantly worse survival, with an overall 3-year survival of 43.4% compared with 68.1% in immunocompetent patients. In our study, patients with stage II disease had improved overall survival versus those with stage I disease, in a statistically significant manner. Patients with stage III disease had significantly worse survival compared with stage I and with stage II. Primary tumor size did not predict nodal involvement. CONCLUSION The data presented represent one of the largest series of primary MCC in the literature and confirm that MCC of all sizes has metastatic potential, supporting sentinel lymph node biopsy for all primary MCC. Because of the unpredictable natural history of MCC, we recommend individualization of care based on the details of each patients tumor and clinical presentation.