Management of advanced non-small-cell lung cancer in elderly populations

Elderly patients, defined as those >or= 70 years of age, represent approximately 40% of all patients diagnosed with non-small-cell lung cancer in the United States. Nonetheless, elderly patients have been underrepresented in national cooperative group trials, and many do not receive appropriate treatment. Whereas the benefit of systemic chemotherapy in younger patients is accepted by most clinicians, there remains a great deal of skepticism with respect to older patients, who are often labeled unfit for chemotherapy. More recent studies with a special focus on elderly patients demonstrate that these patients indeed benefit from chemotherapy. The landmark Elderly Lung Cancer Vinorelbine Italian Study Group trial and the Multicentre Italian Lung Cancer in the Elderly Study clarified the role of vinorelbine in the treatment of elderly patients. Retrospective and prospective subgroup analyses from selected North American trials suggested that elderly patients also benefit from platinum-based combinations. Whether elderly patients should be treated with single-agent versus combination chemotherapy is discussed in this review. The available data suggest that patients should be evaluated for chemotherapy based on their performance status and comorbidities rather than age alone. For elderly patients judged fit to receive combination chemotherapy, carboplatin-based regimens are a reasonable option. In elderly patients with less than optimal performance status or significant comorbid conditions, single-agent therapy may be more appropriate.     

A short study in the treatment of hot flashes with buccal administration of 17-beta estradiol

OBJECTIVE: To assess the efficacy and safety of 17-beta estradiol buccal tablets in reducing hot flush frequency (HFF) in postmenopausal women. METHODS: Estradiol buccal tablets containing 0.05, 0.1, 0.2, or 0.4 mg or placebo were administered for 28 days to 99 postmenopausal women in a randomized, double-blind study; 19 premenopausal women were studied concurrently for comparison of laboratory data. Objective and subjective assessments of HFF were obtained along with measures of estradiol, estrone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH). RESULTS: Measurements of HFF revealed significant decreases from baseline in all estradiol groups (P < 0.01). In the 0.4 mg group, HFF decreased significantly compared to placebo (P < 0.01). All estradiol doses produced similar improvement in the vaginal maturation index. Mean serum estradiol levels increased as doses increased but were lower than in the premenopausal subjects. Mean serum FSH and LH levels decreased in all estradiol groups but not to the levels of the premenopausal subjects; the greatest decrease occurred at the two highest estradiol doses. CONCLUSION: A numerical dose-response relationship with hot flushes was seen in this pilot study comparing 0.05, 0.1, 0.2, and 0.4 mg buccal estradiol. Only 0.4 mg 17-beta estradiol significantly reduced the occurrence of hot flushes compared to placebo.     

Does metformin induce ovulation in normoandrogenic anovulatory women?

OBJECTIVE: This study was undertaken to evaluate the efficacy of metformin in women with anovulation who do not have evidence for hyperandrogenism and classic polycystic ovary syndrome. STUDY DESIGN: A randomized trial of metformin (1500 mg daily) and placebo in 24 anovulatory women was undertaken for 3 months. Assessments of changes in hormone levels and insulin sensitivity were carried out. Abnormal hormonal values were defined by levels exceeding the range in normal ovulatory controls. RESULTS: Anovulatory women had normal androgen levels and luteinizing hormone but had higher serum insulin and lower insulin sensitivity compared with controls. Over 3 months, there were 16 ovulatory cycles with metformin and only 4 with placebo ( P < .05). Success of ovulation did not correlate with changes in androgen, insulin, or insulin sensitivity parameters. CONCLUSION: Metformin may be useful for inducing ovulation in anovulatory women who do not have hyperandrogenism. This effect may be independent of a lowering of androgen or insulin levels.     

Adjuvant activity of Mycobacterium bovis BCG expressing CRM197 on the immune response induced by BCG expressing tetanus toxin fragment C

In order to develop a combined recombinant Mycobacterium bovis BCG (rBCG) vaccine against diphtheria, pertussis and tetanus (DPT), we have constructed different strains of rBCG expressing tetanus toxin fragment C (FC), driven by the up-regulated M. fortuitum beta-lactamase promoter, pBlaF*. Tetanus toxin FC was expressed in comparable levels in native form or in fusion with the beta-lactamase exportation signal sequence; however, in both constructs it was localized to the cytosol. Immunization of mice with rBCG-FC or its combination with rBCG expressing CRM197, induced anti-tetanus toxin antibodies with a Th2 immunoglobulin profile. Administration of a subimmunizing dose of the diphtheria-tetanus toxoid vaccine showed that rBCG-FC primed mice for production of an intense humoral response. Interestingly, the combination of rBCG-FC and rBCG-CRM197 reduced the time required for maturation of the immune response and increased anti-tetanus toxin antibody levels, suggesting adjuvant properties for rBCG-CRM197; this combination induced 75% protection in mice challenged with 100 minimum lethal doses (MLD) of tetanus toxin. Antisera from guinea pigs immunized with this combination were shown to neutralize tetanus toxin and diphtheria toxin. Our results suggest reciprocal adjuvant effects of rBCG-FC and rBCG-CRM197, which may contribute to induction of a more effective immune response against both diseases.     

Female androgen insufficiency: the Princeton consensus statement on definition, classification, and assessment

OBJECTIVE: To evaluate the evidence for and against androgen insufficiency as a cause of sexual and other health-related problems in women and to make recommendations regarding definition, diagnosis, and assessment of androgen deficiency states in women. DESIGN: Evaluation of peer-review literature and consensus conference of international experts. SETTING: Multinational conference in the United States. PATIENT(S): Premenopausal and postmenopausal women with androgen deficiency. INTERVENTION(S): Evaluation of peer-review literature and development of consensus panel guidelines. RESULT(S): The term "female androgen insufficiency" was defined as consisting of a pattern of clinical symptoms in the presence of decreased bioavailable T and normal estrogen status. Currently available assays were found to be lacking in sensitivity and reliability at the lower ranges, and the need for an equilibrium dialysis measure was strongly emphasized. Causes of androgen insufficiency in women were classified as ovarian, adrenal, hypothalamic-pituitary, drug-related, and idiopathic. A simplified management algorithm and clinical guidelines were proposed to assist clinicians in diagnosis and assessment. Androgen replacement is currently available in several forms, although none has been approved for treatment of sexual dysfunction or other common symptoms of female androgen insufficiency. Potential risks associated with treatment were identified, and the need for informed consent and careful monitoring was noted. Finally, the panel identified key goals and priorities for future research. CONCLUSION(S): A new definition of androgen insufficiency in women has been proposed along with consensus-based guidelines for clinical assessment and diagnosis. A simplified management algorithm for women with low androgen in the presence of clinical symptoms and normal estrogen status has also been proposed.     

Effect of bosentan treatment on surrogate markers in pulmonary arterial hypertension

OBJECTIVE: The aim of this study was to evaluate the effect of the oral dual ET(A)/ET(B) receptor antagonist bosentan on different surrogate markers in patients with pulmonary arterial hypertension (PAH). DESIGN AND SETTING: Prospective, open label, uncontrolled study in a University Hospital in Brazil. POPULATION: Fifteen PAH patients (11 females) with mean age of 40 +/- 11 years (5 in WHO functional class II, 10 in class III). METHODS: All patients were investigated at baseline and after 16 weeks of bosentan treatment. We used the following surrogate markers for patients' evaluation: 6-min walk test, quality of life questionnaire (Short Form SF-36) and N-terminal proBNP (B type natriuretic peptide) fraction levels in blood. RESULTS: Between the evaluation at baseline and week 16, the 6-min walk test distance changed from 396 +/- 135 to 434 +/- 137 m (p < 0.05). Each of the eight domains of the SF-36 was significantly improved. Mean NT-proBNP levels were decreased from a mean of 1670 pg/mL to 1010 pg/mL (p = 0.01). CONCLUSION: The study suggests that bosentan treatment results in the improvement of different kinds of surrogate markers independently of their specificity to reflect functional capacity, quality of life and myocardial stress. It is concluded that the combined use of these different markers may be an alternative endpoint for future short duration clinical trials.     

Measuring clinically significant chemotherapy-related toxicities using Medicare claims from Cancer and Leukemia Group B (CALGB) trial participants

BACKGROUND: Because the elderly are underrepresented on clinical trials, physicians have few sources of information to estimate the risks (ie, toxicities) and benefits of chemotherapy administration to the elderly. OBJECTIVE: Our goal was to determine whether the standard measures of toxicity used in clinical trials could be captured from observational Medicare claims data. METHODS: We identified 175 elderly clinical trial patients treated on 2 Cancer and Leukemia Group B (CALGB) trials (9344, adjuvant breast study and 9730, advanced lung cancer study) and merged participants' CALGB data with their Medicare data. From CALGB data, we identified the most frequent Extended Clinical Toxicity Critieria grade III/IV toxicities. We reviewed diagnostic and procedure codes from Medicare manuals, developed algorithms to measure the toxicities, and then finalized the algorithms after empiric review of patients' codes. We compared results of Medicare algorithms to gold standard CALGB toxicity information to calculate test characteristics. RESULTS: CALGB data documented that 15 grade III/IV chemotherapy-related toxicities occurred in > or =3% of the 175 patients: white blood cell, hemoglobin, platelets, anorexia, nausea, vomiting, diarrhea, stomatitis, sensory neuropathy, motor neuropathy, motor or sensory neuropathy, dyspnea, hyperglycemia, infection, and malaise. Vomiting was the only toxicity identified by the Medicare-based algorithm with a sensitivity, specificity, and area under the receiver operator curve of > or =80%. CONCLUSIONS: The results of this preliminary study suggest that Medicare diagnostic and procedure codes may be of only limited value in measuring clinically significant chemotherapy-related toxicities in elderly Medicare beneficiaries. Future research includes confirming these findings in a larger and more diverse sample.