Final results from the PERUSE study of first-line pertuzumab plus trastuzumab plus a taxane for HER2-positive locally recurrent or metastatic breast cancer, with a multivariable approach to guide prognostication.

BACKGROUND: The phase III CLinical Evaluation Of Pertuzumab And TRAstuzumab (CLEOPATRA) trial established the combination of pertuzumab, trastuzumab and docetaxel as standard first-line therapy for human epidermal growth factor receptor 2 (HER2)-positive locally recurrent/metastatic breast cancer (LR/mBC). The multicentre single-arm PERtUzumab global SafEty (PERUSE) study assessed the safety and efficacy of pertuzumab and trastuzumab combined with investigator-selected taxane in this setting. PATIENTS AND METHODS: Eligible patients with inoperable HER2-positive LR/mBC and no prior systemic therapy for LR/mBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab and pertuzumab until disease progression or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Prespecified subgroup analyses included subgroups according to taxane, hormone receptor (HR) status and prior trastuzumab. Exploratory univariable analyses identified potential prognostic factors; those that remained significant in multivariable analysis were used to analyse PFS and OS in subgroups with all, some or none of these factors. RESULTS: Of 1436 treated patients, 588 (41%) initially received paclitaxel and 918 (64%) had HR-positive disease. The most common grade ≥3 adverse events were neutropenia (10%, mainly with docetaxel) and diarrhoea (8%). At the final analysis (median follow-up: 5.7 years), median PFS was 20.7 [95% confidence interval (CI) 18.9-23.1] months overall and was similar irrespective of HR status or taxane. Median OS was 65.3 (95% CI 60.9-70.9) months overall. OS was similar regardless of taxane backbone but was more favourable in patients with HR-positive than HR-negative LR/mBC. In exploratory analyses, trastuzumab-pretreated patients with visceral disease had the shortest median PFS (13.1 months) and OS (46.3 months). CONCLUSIONS: Mature results from PERUSE show a safety and efficacy profile consistent with results from CLEOPATRA and median OS exceeding 5 years. Results suggest that paclitaxel is a valid alternative to docetaxel as backbone chemotherapy. Exploratory analyses suggest risk factors that could guide future trial design.

Anti-NaPi2b antibody-drug conjugate lifastuzumab vedotin (DNIB0600A) compared with pegylated liposomal doxorubicin in patients with platinum-resistant ovarian cancer in a randomized, open-label, phase II study.

Background: Lifastuzumab vedotin (LIFA) is a humanized anti-NaPi2b monoclonal antibody conjugated to a potent antimitotic agent, monomethyl auristatin E, which inhibits cell division by blocking the polymerization of tubulin. This study is the first to compare an antibody-drug conjugate (ADC) to standard-of-care in ovarian cancer (OC) patients. Patients and methods: Platinum-resistant OC patients were randomized to receive LIFA [2.4 mg/kg, intravenously, every 3 weeks (Q3W)] or pegylated liposomal doxorubicin (PLD) (40 mg/m2, intravenously, Q4W). NaPi2b expression and serum CA-125 and HE4 levels were assessed. The primary end point was progression-free survival (PFS) in intent-to-treat (ITT) and NaPi2b-high patients. Results: Ninety-five patients were randomized (47 LIFA; 48 PLD). The stratified PFS hazard ratio was 0.78 [95% confidence interval (95% CI), 0.46-1.31; P = 0.34] with a median PFS of 5.3 versus 3.1 months (LIFA versus PLD arm, respectively) in the ITT population, and 0.71 (95% CI, 0.40-1.26; P = 0.24) with a median PFS of 5.3 months versus 3.4 months (LIFA versus PLD arm, respectively) in NaPi2b-high patients. The objective response rate was 34% (95% CI, 22% to 49%, LIFA) versus 15% (95% CI, 7% to 28%, PLD) in the ITT population (P = 0.03), and 36% (95% CI, 22% to 52%, LIFA) versus 14% (95% CI, 6% to 27%, PLD) in NaPi2b-high patients (P = 0.02). Toxicities included grade ≥3 adverse events (AEs) (46% LIFA; 51% PLD), serious AEs (30% both arms), and AEs leading to discontinuation of drug (9% LIFA; 8% PLD). Five (11%) LIFA versus 2 (4%) PLD patients had grade ≥2 neuropathy. Conclusion: LIFA Q3W was well tolerated and improved objective response rate with a modest, nonstatistically significant improvement of PFS compared with PLD in platinum-resistant OC. While the response rate for the monomethyl auristatin E-containing ADC was promising, response durations were relatively short, thereby highlighting the importance of evaluating both response rates and duration of response when evaluating ADCs in OC. Clinical trials.gov: NCT01991210.

Preference for subcutaneous or intravenous administration of rituximab among patients with untreated CD20+ diffuse large B-cell lymphoma or follicular lymphoma: results from a prospective, randomized, open-label, crossover study (PrefMab).

Background: The aim of this study was to evaluate patient preference and satisfaction for the subcutaneous (s.c.) versus intravenous (i.v.) formulation of rituximab given with chemotherapy in previously untreated patients with CD20+ diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL). Patients and methods: Patients received eight cycles of rituximab according to 2 schedules: Arm A received 1 cycle rituximab i.v. (375 mg/m2) and 3 cycles rituximab s.c. (1400 mg) then 4 cycles rituximab i.v.; Arm B received 4 cycles rituximab i.v. (375 mg/m2) then 4 cycles rituximab s.c. (1400 mg). Alongside rituximab, both arms received 6-8 cycles of chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP), cyclophosphamide, vincristine, prednisone (CVP), or bendamustine as per standard local practice). Preference for s.c. or i.v. administration was evaluated using the Patient Preference Questionnaire (PPQ) at cycles 6 and 8. Patient satisfaction and convenience were assessed using the Cancer Therapy Satisfaction Questionnaire (CTSQ), and Rituximab Administration Satisfaction Questionnaire (RASQ) at cycles 4 and 8. Results: At the primary data cut-off (19 January 2015), the intent-to-treat population comprised 743 patients. The majority had DLBCL (63%) and baseline characteristics were balanced between arms. At cycle 8, 81% of patients completing the PPQ preferred rituximab s.c. Preference was not impacted by treatment sequence or disease type. Patient satisfaction as measured by RASQ was higher for s.c. versus i.v. CTSQ scores were similar between arms. Adverse events were generally balanced between administration routes and no new safety signals were detected. Conclusion: Most previously untreated patients with CD20+ DLBCL or FL preferred s.c. to i.v. rituximab administration. Patient satisfaction with rituximab treatment was generally greater with s.c. administration. Registered clinical trial number: NCT01724021 (ClinicalTrials.gov).

Assessment of psychological distress in prospective bone marrow transplant patients.

Patient psychological distress is associated with many aspects of the bone marrow transplantation (BMT) process and has been linked with poor treatment outcomes. We assessed psychological distress in potential BMT candidates, and compared patient and nurse coordinator ratings of emotional distress at the time of initial BMT consultation. Fifty patients self-reported psychological distress using both the NCCN Distress Thermometer (DT) and the Hospital Anxiety and Depression Scale (HADS). Coordinators rated patient emotional distress using the DT and Coordinator Rating Scales that measure anxiety and depression. Fifty and 51% of patients self-reported clinically significant levels of emotional distress and anxiety, respectively, but only 20% self-reported clinically significant levels of depression. There was good correlation between ratings using the brief DT and the more comprehensive HADS. There was significant but only moderate agreement between patient and coordinator ratings of emotional distress and anxiety, with coordinators underestimating the number of patients with high levels of emotional distress. In addition, coordinator ratings of patient emotional distress primarily reflected anxiety, whereas anxiety and depression together only minimally accounted for patient self-reports of psychological distress. These findings suggest that: (1) the DT can be a useful screening device; (2) approximately half of patients at the time of initial consultation for BMT already experience significant levels of psychological distress; and (3) coordinators observe emotional distress primarily as anxiety, but patients experience psychological distress as something more than anxiety and depression.

Comparison of headache parameters using headache type and emotional status.

OBJECTIVE: The literature on the impact of headache has traditionally focused on the relationship of subject variables to specific headache types. Recently, increasing attention is being paid to the impact on disease of emotional distress. The current study was designed to determine whether differences in subject variables arose when comparing them by headache type vs. empirically derived emotional distress clusters. METHOD: A review of responses to measures of headache impact (e.g., duration, medication use) and emotional distress (Brief Symptom Inventory, BSI) completed by 292 patients attending a headache clinic was conducted. Patient responses were analyzed by headache type and emotional distress cluster. RESULTS: Comparison by headache type revealed that combined headaches were of longer duration, used more medications, and were more likely to have seen a chiropractor. Comparison by distress cluster revealed high-distress patients to have missed more days of work, have legal involvement, have sought psychological services, and to be male. CONCLUSION: The results suggest that clinically useful information can be obtained by using both headache diagnosis and emotional status. In addition, this information may be useful by providing additional knowledge that may lead to different clinical protocols in headache management.

Cancer-specific worry interference in women attending a breast and ovarian cancer risk evaluation program: impact on emotional distress and health functioning.

Intrusive thoughts about cancer, often identified as 'cancer-specific worries' or 'cancer-specific distress', have been postulated to be associated with dysfunction in women at increased risk of developing breast or ovarian cancer. The current study discusses the development and validation of a measure designed to assess women's perceptions of the interference such worries create in their daily functioning. Analyses revealed that approximately two-thirds of a high-risk breast cancer clinic sample perceived worries about breast cancer as interfering with their functioning across a variety of life domains. Multiple regression analyses indicated that worry interference scores predicted Profile of Mood States (POMS) Anxiety and Confusion, and Short Form-36 (SF-36) Role-Emotional and Mental Health scores after the effects of other variables such as frequency of worry about breast cancer, and having a family history of cancer had been considered. Women who perceived their worries as interfering with their functioning reported higher levels of anxiety and confusion, and diminished mental health and role functioning. The results add to the expanding area of anxiety/distress in at-risk populations by providing (1) a direct measure of the perceived interference associated with breast cancer-specific thoughts, (2) a validation of the measure via its associations with standard measures of emotional distress and health functioning, and (3) evidence of the measure's incremental predictive value in explaining distress and quality of life, after consideration of background variables, such as having a family history of cancer.

Psychosocial characteristics of individuals with non-stage IV melanoma.

PURPOSE: Melanoma is the fastest growing solid tumor among men and women and accounts for 79% of skin cancer-related deaths. Research has identified that distress is frequently associated with a diagnosis of cancer and may slow treatment-seeking and recovery, increasing morbidity and even mortality through faster disease course. Given that the 5-year survival rates for individuals with melanoma are determined primarily by the depth and extent of spread, distress that interferes with seeking treatment has the potential to be life-threatening. PATIENTS AND METHODS: The current study was designed to identify levels of distress present in individuals seeking treatment at a large, Midwestern, multidisciplinary melanoma clinic. It also focused on determining the quality of life, level of anxiety, and coping strategies used by individuals with melanoma before treatment. Given that the course of treatment and outcome for patients with stage IV disease is vastly different from that of patients with stages I to III disease, they were excluded from the study. RESULTS: Results indicated that most individuals who are presenting to a melanoma clinic do not report a clinically significant level of distress. However, there is some variability in this, with 29% of patients reporting moderate to high levels of distress. Moreover, analyses suggest that distressed individuals are more likely to use maladaptive coping strategies, such as escape-avoidance coping, and to have poorer quality of life. CONCLUSION: Although most individuals do not present with significant levels of distress, a significant minority are distressed and rely more heavily on coping strategies that do not benefit them. Such individuals would likely benefit most from psychological intervention.

Personality predictors of mortality in cardiac transplant candidates and recipients.

OBJECTIVES: Emotional factors are generally recognized as impacting the care of end-stage heart disease and mortality following cardiac transplants. Equally important, however, are predictors of pretransplant mortality. The current study examined the utility of the Millon Behavioral Health Inventory (MBHI) as a predictor of pre- and posttransplant mortality. METHODS: A total of 103 cardiac transplant candidates were assessed with the MBHI as part of a pretransplant evaluation that included baseline demographic variables and cardiac status. Time to transplant and mortality status at 1 and 5 years was also obtained. RESULTS: Cluster analysis of MBHI response scores elicited two clusters characterized by high and low distress. Cluster membership predicted survival status at 1-year and 5-year follow-up, with high distress cluster patients having significantly higher mortality in both the total sample and a subgroup of patients who did receive a heart transplant. CONCLUSIONS: These results support the value of the MBHI for assessing personality attributes that may dispose toward unfavorable outcome in heart transplant candidates. Further understanding of psychosocial contributions to illness course and outcome may enable more effective selection of treatment interventions with cardiac patients.

Psychiatric side effects of interferon therapy: prevalence, proposed mechanisms, and future directions.

The increasing use of interferon (IFN) in treating a variety of disorders including, malignant melanoma and hepatitis C, has resulted in the identification and increasing concern about the psychiatric side effects that can result from treatment. These effects can occur either shortly after beginning IFN therapy or later as a result of continued treatment. Studies have reported the incidence of later side effects, which include symptoms of depression, anxiety, and occasional suicidal ideation, to be from 0% to 70%. Case studies have demonstrated that pharmacologic interventions are beneficial in reducing iatrogenic psychiatric symptoms while allowing patients to maintain IFN therapy. The present article provides an overview of the psychiatric effects of IFN therapy, the proposed mechanisms of these side effects, and case studies that provide mechanistic support. In addition, limitations of the current literature are provided with suggestions for treating physicians and a discussion of possible future research directions.

Orthodontic positioner used for home fluoride treatments.

It has been well documented that the more time the enamel surface is exposed to fluoride, the higher will be the caries protection. An extremely good method of greatly increasing caries resistance is by daily or weekly home fluoride treatments. This procedure is usually limited to special cases of rampant caries, patients with hemophilia, and handicapped patients in whom caries control is vital. It is not used more widely because of the added costs of impressions, tray fabrication, and professional. If the patient already has a vehicle for applying fluoride, such as a positioner or mouth guard, it is a simple matter to prescribe or dispense fluoride gel to be used when these appliances are being worn. This is expecially true for orthodontic postioners. When bands are removed, a slight space usually exists interproximally. This space greatly facilitates fluoride contact with the proximal surfaces. Fluoride will tend to recalcify decalcified areas of enamel in addition to providing added caries protection for the patient. If positioners are not used after band removal, home fluoride trays or rinses can also be effective. Since many orthodontic patients wear a positioner when bands are removed, the orthodontist can provide his patients with the benefits of topical fluoride by prescribing fluoride gel and explaining how to use it along with his positioner.