Resectable non-small cell lung cancer in the elderly: is there a role for adjuvant treatment?

Over the past 2 years, systemic chemotherapy has emerged as the standard adjuvant approach for resectable non-small cell lung cancer (NSCLC). In aggregate, a 5.3% improvement in 5-year survival has been observed with platinum-based combination chemotherapy in patients with NSCLC, with benefits being most pronounced in stage II and IIIa disease. Recent data suggest that the elderly (up to age 75 years) derive benefits from such therapy similar to those seen in younger patients. Unfortunately, although patients aged >or=70 years constitute 50% of those with newly diagnosed NSCLC, <10% of enrollees in clinical trials are in this age group. To help offset the spectre of increased risk in this age group, two potential strategies exist: (i) substitution of carboplatin for cisplatin; and (ii) increased use of neoadjuvant treatment to avoid perioperative co-morbidities and difficulties with compliance that can hamper appropriate administration of adjuvant treatment. To date, there have been no elderly-specific adjuvant trials in NSCLC. Over time, this omission is likely to be corrected.     

Cannabinoids: is there a potential treatment role in epilepsy?

Cannabinoids have been used medicinally for centuries, and in the last decade, attention has focused on their broad therapeutic potential particularly in seizure management. While some cannabinoids have demonstrated anticonvulsant activity in experimental studies, their efficacy for managing clinical seizures has not been fully established. This commentary will touch on our understanding of the brain endocannabinoid system’s regulation of synaptic transmission in both physiological and pathophysiological conditions, and review the findings from both experimental and clinical studies on the effectiveness of cannabinoids to suppress epileptic seizures. At present, there is preliminary evidence that non-psychoactive cannabinoids may be useful as anticonvulsants, but additional clinical trials are needed to fully evaluate the efficacy and safety of these compounds for the treatment of epilepsy.     

Agitation in the demented elderly: a role for benzodiazepines?

"Agitation" is a term that is used to describe a wide range of dysfunctional behaviours in geriatric populations. The term is so widely used that in many cases it loses clinical meaning and therefore a more restricted use of the term is suggested. When patients with agitation are identified it is important to look for underlying treatable pathology which is often present. Controversy surrounding the most appropriate medications is reviewed with particular reference to both neuroleptics and benzodiazepines. A randomized double-blind comparison of lorazepam and alprazolam in demented patients with agitation was carried out. While both drugs were efficacious for some patients, there were significantly more serious side-effects with lorazepam. It appears that there is a role for benzodiazepines such as alprazolam in the management of the agitated demented patient.     

Is there a growing role for endocrine therapy in the treatment of breast cancer?

Novel biochemical findings on the molecular mechanisms of estrogen actions may help us to understand some of the unexplained observations seen in breast cancer treatment and suggest new therapeutic opportunities. Thus, apart from the challenge of improving the clinical treatment of patients with advanced disease, results from trials in this setting may reveal new therapeutic principles that may be evaluated in the adjuvant setting. The role of endocrine therapy in metastatic as well as early breast cancer is increasing, and the possibility of improving cure rates for breast cancer by implementing therapy with novel aromatase inhibitors in the adjuvant setting is exciting. While the results from prevention trials are most interesting, suggesting the possibility of reducing breast cancer incidence in high-risk groups, more data are needed before we can decide whether such interventions are warranted in women at high risk of developing breast cancer.     

Is there a role for a mucosal influenza vaccine in the elderly?

Influenza infection is an acute respiratory disease with a high morbidity and significant mortality, particularly among the elderly and individuals with chronic diseases. The majority of countries now recommend annual influenza vaccination for all people aged 65 years or older, and for those with high risk conditions. Most commercially available influenza vaccines are administered systemically and while these are effective in children and young adults, efficacy levels in elderly individuals have been reported to be much lower. Mucosal vaccines may offer an improved vaccine strategy for protection of the elderly. As the influenza virus causes a respiratory infection, it is potentially more beneficial to administer a vaccine that will boost protection in the mucosal surfaces of the upper and lower respiratory tract. Mucosal influenza vaccines are aimed at stimulating protective immunity in the respiratory tract via oral or intranasal immunisation. This review examines our present knowledge of mucosal immunity and current strategies for mucosal vaccination. It also stresses that the use of serum antibody levels as a 'surrogate marker' for protection against influenza is potentially misleading; serum antibody, for example, may be a quite inappropriate marker to assess a mucosal vaccine. This marker does not reflect other immune responses to vaccination that are crucial for protection.     

Is there a role for immunoconjugates in the treatment of AIDS?

The use of antibodies to deliver therapeutic agents to specific cells is a well-established concept in the treatment of malignancy. Therapeutic effects have been shown in both animal models and human clinical trials. By analogy, antibodies and other ligands may be used to treat AIDS by targeting cells that are actively producing HIV and spreading the infection. Immunoconjugates with specificity for HIV antigens or structures on the surface of HIV-infected cells have been made. These agents have undergone extensive in vitro testing. In tissue culture they can eliminate infected cells and halt the production of HIV. A number of agents have been shown to enhance the efficacy of anti-HIV immunoconjugates. Because animal models of HIV-infection are problematic, there has been little preclinical testing. Nevertheless, several clinical trials have begun.     

Colorectal cancer in the elderly: is palliative chemotherapy of value?

Colorectal cancer is a disease of the elderly, with 70% of patients being aged 65 years or older. In Western countries, the total number of elderly patients with this disease is expected to further increase in the future. Since the incidence of adverse physical or socioeconomic conditions in the elderly is higher than in younger patients, a thorough assessment of the patient's suitability for therapy should be performed before a decision is made. Using a Comprehensive Geriatric Assessment (CGA) to subdivide the population of elderly cancer patients into three groups can help to guide treatment decisions. Both in the adjuvant and in the palliative setting, there are sufficient data supporting the use of fluorouracil-based chemotherapy in fit elderly patients who can tolerate cytotoxic treatment. Systemic chemotherapy has been shown to effectively reduce mortality in the adjuvant situation and to be of clinical benefit for patients with metastatic disease in terms of longer survival, control of symptoms and quality of life. In recent years, new substances such as oxaliplatin or irinotecan have shown significant activity in the treatment of patients with metastatic colorectal cancer. However, information on how to guide the use of these new drugs in elderly patients is still lacking. Limited data from clinical trials indicate treatment efficacy in selected elderly patients comparable to that observed in younger patients, with overall manageable toxicity. Clearly, further clinical trials in elderly patients with colorectal cancer are necessary as well as the incorporation of aspects of geriatric medicine into the teaching programme of medical oncologists.     

Anti-oxidant therapy: does it have a role in the treatment of human disease?

Free radical oxidative stress has been implicated in the pathogenesis of a variety of human diseases. Natural anti-oxidant defences have also been found to be defective in many of the same diseases. Many researchers have concluded that, if the imbalance between the oxidative stresses and anti-oxidant defence can be corrected by supplementing natural anti-oxidant defences, it may be possible to prevent or retard disease progression. Potential anti-oxidant therapies include natural anti-oxidant enzymes and vitamins or synthetic agents with anti-oxidant activity. Diseases where anti-oxidant therapy may be beneficial can be divided into those involving acute intervention, such as reperfusion injury or inflammation, and those involving chronic preventative therapy, such as atherosclerosis, carcinogenesis and diabetic vascular disease. The pharmaceutical considerations are different in each case. The principles guiding the development, use and assessment of anti-oxidant therapies are discussed in this review.     

18-Methoxycoronaridine: a potential new treatment for obesity in rats?

Rationale  Excessive eating often leads to obesity. Although a variety of neurotransmitters and brain regions are involved in modulating food intake, a role of accumbal dopamine is thought to be critical for several aspects of this behavior. Since 18-methoxycoronaridine (18-MC), a selective antagonist of α3β4 nicotinic receptors, was previously shown to alter dopamine release in the nucleus accumbens in response to chronic injections of cocaine and morphine, this drug could be a promising therapy for abnormal eating behavior. Objectives  Assess the effect of 18-MC on the consumption of sucrose (15%) vs. water in a self-administration paradigm and on the intake of freely available palatable fluids (i.e., 5% sucrose, 0.1% saccharin, and 0.6% saline solutions) as well as on water intake. Determine whether repeated administration of 18-MC (20 mg/kg i.p.) affects weight gain, food intake, and fat deposition in rats drinking 30% sucrose solution. Results  Acute administration of 18-MC (10–40 mg/kg i.p.) reduced operant responding for sucrose and decreased ad libitum ingestion of sucrose, saccharin, and saline. The highest dose of 18-MC also reduced consumption of water when palatable fluids were not available. In rats having unlimited access to sucrose (30%), chronic treatment with 18-MC (20 mg/kg i.p.) prevented sucrose-induced increases in body weight, decreased fat deposition, and reduced consumption of sucrose while not altering food intake. Conclusions  These data suggest that antagonism of α3β4 nicotinic receptors may be involved in the regulation of intake of palatable substances regardless of its caloric value and may participate in maintaining obesity.     

Thalidomide: a new anticancer drug?

Experimental studies have demonstrated that thalidomide (Thal), a drug developed as a sedative, has antitumoural properties. The possible antitumour mechanisms of action involve: inhibition of angiogenesis, cytokine-mediated pathways, modulation of adhesion molecules, inhibition of cyclooxygenase-2 and stimulation of immuno response. Therefore, Thal is under clinical evaluation in oncology. This paper provides an overview of the data currently available in literature regarding, in terms of activity and toxicity, the use of Thal in cancer patients. Multiple myeloma is so far the most responsive malignancy. A moderate activity has been documented in certain solid tumours: glioblastoma multiforme, renal cell carcinoma and malignant melanoma. Tolerability is generally satisfactory with peripheral neuropathy being the most relevant dose-dependent toxicity. The more frequent, but moderate side effects are: somnolence, constipation, dizziness and fatigue. More studies are needed to properly evaluate the anticancer activity of Thal alone or in combination with other anticancer treatments. Preliminary studies suggest promising results of Thal in combinations with corticosteroids and cytotoxic drugs as front-line therapy of multiple myeloma. Regarding therapy of solid tumours in the adult, combination with chemotherapy, radiation therapy and molecular-targeting compounds are under investigation.     

Do beta-blockers have a role in the treatment of chronic heart failure?

There has been growing interest in and recognition of the role of beta-blockers in chronic heart failure (CHF). The mode of action is complex and several mechanisms have been proposed. The principal rationale for the use of beta-blockade is to counteract neurohormonal activation and its deleterious consequences in CHF. While the positive effect of this treatment on haemodynamics, exercise tolerance and quality of life, and a clear trend in favour of improved prognosis have been shown, there is still no concrete proof that beta-blockers reduce mortality in CHF. Several large-scale, prospective, randomised, placebo-controlled trials, designed to provide a definitive answer, are underway.     

Could nanoparticle systems have a role in the treatment of cerebral gliomas?

Malignant brain tumors are difficult to manage clinically and are associated with high rates of morbidity and mortality. Late diagnosis and the limitations of conventional therapies that may result from inefficient delivery of the therapeutic or contrast agent to brain tumors due to the blood-brain barrier and nonspecificity of the agents, are major reasons for this unsolved clinical problem. Nanotechnology involves the design, synthesis, and characterization of materials and devices that have a functional organization in at least one dimension on the nanometer scale. The nanoparticle has emerged as a potential vector for brain delivery, able to overcome the difficulties of modern strategies. Moreover, multifunctionality can be engineered into a single nanoplatform so that it can provide tumor-specific detection, treatment, and follow-up monitoring. This review reports the latest research in nanoparticle-based glioma treatment. FROM THE CLINICAL EDITOR: In recent years, nanoparticles have emerged as potential delivery vectors targeting brain tumors, including multifunctional NP-s allowing tumor-specific detection, treatment, and follow-up monitoring. This review summarizes the latest research in nanoparticle-based glioma treatment.     

Donepezil in a chronic drug user—a potential treatment?

The objective of the current study was to explore the potential cognitive benefits of an anticholinesterase inhibitor, donepezil, in a former chronic drug user. A neuropsychological test battery composed of the vocabulary and matrix reasoning subtests of the Wechsler adult intelligence scale-III, measures of everyday executive functioning (behavioural assessment of the dysexecutive syndrome [BADS]), and verbal learning and memory tasks (California verbal learning test-II; Rivermead behavioural memory test) was completed at baseline, at 3 months after introducing donepezil, and at 3 months after donepezil was discontinued. After donepezil treatment, substantial improvements were found on tasks of nonverbal fluid reasoning (i.e. matrix reasoning) and other executive functioning tests (i.e. BADS). At entry into the study, poor academic performance and subjective problems with memory and concentration were reported, particularly after amphetamine use (i.e. MDMA and crystal methamphetamine); after donepezil treatment, dramatic increases in memory, concentration and academic achievement were observed. The finding of improvements in tests of executive functioning and in academic performance in this case study, together with the minimal adverse side effects of donepezil, warrants the investigation of controlled studies of cholinergic enhancement in chronic amphetamine and other drug users.     

Influenza vaccination and antiviral therapy: is there a role for concurrent administration in the institutionalised elderly?

Influenza vaccination is estimated to be 50-68% efficacious in preventing pneumonia, hospitalisation or death in nursing home residents. Large culture-proven outbreaks may occur despite high resident vaccination rates. There is, therefore, a significant role for concurrent administration of influenza vaccination and antiviral therapy. The use of antiviral treatment and chemoprophylaxis requires community reporting of viral isolates, and contingency plans for rapid case identification and application of antiviral therapy. Clinicians must react quickly to control a highly infectious seasonal pathogen that may strike as an explosive outbreak. This situation is unique in geriatric practice. Current antiviral treatment should be administered within 48 hours of symptom onset, and is more efficacious if administered within 12 hours. In the case of an explosive institutional outbreak, a 1-day delay in prophylaxis may allow infection of many residents with a potentially fatal illness. Influenza must be differentiated from other respiratory viruses or syndromes. Grouped rapid diagnostic tests can aid laboratory confirmation. Antiviral agents include the M(2) inhibitors, amantadine and rimantadine, active against influenza A, and the neuraminidase inhibitors, zanamivir and oseltamivir, active against influenza A and B. In our experience, influenza B illness is as severe as influenza A. All agents have similar efficacy as treatment and prophylaxis against sensitive strains. When M(2) inhibitors are used simultaneously within an enclosed space (i.e. household or nursing home) as both treatment and prophylaxis, resistant strains may emerge that limit prophylactic efficacy. When M(2) inhibitors are administered to suspected cases (residents or staff) in institutions, precautions against secretion are especially important to diminish the risk of transmission of resistant virus. Rimantadine has been shown to have significantly fewer CNS adverse events compared with amantadine. Amantadine and oseltamivir require dosage adjustment in those with renal impairment. Oseltamivir, rimantadine and amantadine are administered by mouth, while zanamivir is administered by oral inhalation in a lactose powder. The labelling advises caution in the use of zanamivir in those with underlying airway disease. Pooled analysis of studies in patients given zanamivir indicate that individuals over the age of 50 years (at high risk for complications) and those severely symptomatic at presentation, tend to benefit most from early treatment. Neuraminidase inhibitors also diminish the need for antibacterials to treat secondary complications. An institutional programme to control influenza should include vaccination, and contingency plans for clinical surveillance, specimen processing and the rapid application of antiviral treatment and prophylaxis.     

Lipid lowering therapy in the elderly: is there a benefit?

The rising number of elderly people has a major impact on healthcare systems. Advancing age is a risk factor for the development of cardiovascular disease (CVD), which represents a major global healthcare problem. The clinical efficacy and safety of lipid lowering treatment (especially statins) is well established following a series of large-scale, randomised controlled trials, which mainly recruited patients under the age of 70 years. Subgroup analyses together with the findings of trials involving sufficient numbers of elderly participants, such as the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) and the Heart Protection Study (HPS) offer a basis for considering statin therapy in this population. Furthermore, since this population is at greater absolute risk of CVD, substantial benefits from adequate treatment may be anticipated. However, underevaluation and undertreatment appear to be common in the elderly. In this review, we provide a survey of potentially modifiable cardiovascular risk factors in association with old age, and discuss the relevant findings of large-scale end-point clinical studies as well as major considerations regarding lipid-lowering treatment in this population. It is concluded that the decision whether to treat hypercholesterolaemia in the elderly is currently individualised, depending upon the degree of risk, general health, willingness to receive treatment and financial concerns. Further, prospective randomised trials are required to guide physicians towards an effective management of older individuals at increased atherosclerotic risk.     

Do sunscreens have a role in preventing skin cancer?

Solar ultraviolet (UV) radiation is largely responsible for the harmful effects of sun exposure, notably sunburn, photosensitivity and skin cancer. UV radiation is, for example, implicated in malignant melanoma (the most serious form of skin cancer), the incidence of which has risen in the UK over the last 30 years. Such risks make it crucial to know whether measures aimed at reducing sun damage offer worthwhile benefit. Here we assess whether the sunscreen products commonly used to prevent sunburn have a place in the prevention of skin cancer.     

Cyclo-oxygenase-2 and its inhibition in cancer: is there a role?

Despite recent improvements in chemotherapy and radiation therapy in cancer management with the addition of biological agents, novel treatment approaches are needed to further benefit patients. Cyclo-oxygenase (COX)-2 inhibition represents one such possibility. COX-2 is an enzyme induced in pathological states such as inflammatory disorders and cancer, where it mediates production of prostanoids. The enzyme is commonly expressed in both premalignant lesions and malignant tumours of different types. A growing body of evidence suggests an association of COX-2 with tumour development, aggressive biological tumour behaviour, resistance to standard cancer treatment, and adverse patient outcome. COX-2 may be related to cancer development and propagation through multiple mechanisms, including stimulation of growth, migration, invasiveness, resistance to apoptosis, suppression of the immunosurveillance system, and enhancement of angiogenesis. Epidemiological data suggest that NSAIDs and selective COX-2 inhibitors might prevent the development of cancers, including colorectal, oesophageal and lung cancer. Preclinical investigations have demonstrated that inhibition of this enzyme with selective COX-2 inhibitors enhances tumour response to radiation and chemotherapeutic agents. These preclinical findings have been rapidly advanced to clinical oncology. Clinical trials of the combination of selective COX-2 inhibitors with radiotherapy, chemotherapy or both in patients with a number of cancers have been initiated, and preliminary results are encouraging. This review discusses the role of COX-2, its products (prostaglandins) and its inhibitors in tumour growth and treatment.