The use of surgery in mesothelioma.

meso sx

Malignant pleural mesothelioma is an aggressive cancer of the pleura that is associated with exposure to fibrous minerals in the environment, such as asbestos or erionite. Because asbestos is ubiquitous in building material, the worldwide incidence of the disease continues to rise; rates in Europe are expected to increase by 5—10% per year for the next 25 years.1 Left untreated, the prognosis of malignant pleural mesothelioma is poor, with median overall survival of 7 months.1 Diagnosis of early disease is rare, because symptoms, such as dyspnoea or chest wall pain, often do not occur until later stages. Suspicion must be high to make the diagnosis, because the disease often presents as a pleural effusion or pleural thickening on imaging, or both, making it difficult to differentiate from other diseases.2

Once malignant pleural mesothelioma is suspected, a tissue sample is obtained in the operating room via pleuroscopy or video-assisted thoracoscopy, with incisions placed in a potential future thoracotomy site.1 Pleural fluid cytology and needle biopsy are often insufficient, because adequate specimens are needed to establish whether invasion is present and distinguish malignant disease from fibrous exudate or proliferating mesothelial cells. Additionally, enough tissue should be obtained to identify the histological subtype: epithelial, sarcomatoid, or mixed (biphasic).23

Prognostic factors that portend increased survival include epithelial histology, female sex, and earlier stage. In a retrospective study of 945 patients,4 longer survival was associated with these characteristics, as well as no history of smoking or asbestos exposure, and left-sided tumours. The longest survival is recorded in women younger than 50 years and those with epithelial disease, for whom median survival exceeds 30 months.5 The difference between the sexes is a consistent finding and suggests that circulating oestrogen might affect tumour biology.356

While trials assess the roles of neoadjuvant or adjuvant chemotherapy, radiation therapy, intracavitary chemotherapy, photodynamic therapy, and other systemic options, the standard of care is resection and adjuvant therapy with radiation or chemotherapy, or both.6 Most studies have suggested that patients with favourable disease characteristics benefit from surgery with curative intent in the context of multimodality therapy.127

The two options for surgical resection are extrapleural pneumonectomy (EPP) and pleurectomy/decortication (P/D). With EPP, the pleural envelope is resected along with its contents, including the lung, diaphragm, and pericardium. P/D is a similar radical resection, but preserves the lung. Until 10 years ago, many surgeons preferred EPP for macroscopic complete resection, even in early-stage disease, as long as the patient had adequate cardiopulmonary function. Critics of EPP suggested that it was associated with high risk and did not offer a clear survival benefit. The Mesothelioma and Radical Surgery trial8 was designed to assess the role of EPP in malignant pleural mesothelioma, but its design was not feasible due to the high morbidity associated with EPP, and subsequent exploratory analyses were done with sample sizes that did not have adequate power to draw meaningful conclusions.

Many surgeons have recognised that macroscopic complete resection can be accomplished with P/D and with less morbidity than with EPP, particularly for early-stage disease. A multi-institutional retrospective study of 663 patients9 showed that, when undertaken as part of a multimodality treatment plan with curative intent, cumulative survival for early-stage disease was higher for P/D than for EPP. For later-stage disease, survival was higher with EPP. A subsequent study3 assessed 42 patients with International Mesothelioma Interest Group stage III disease undergoing P/D and adjuvant chemoradiation. Macroscopic complete resection was possible in 26 (62%), and median survival after this procedure was 35 months compared with 13 months in the 16 patients with incomplete resections.3 These data suggest that, as long as macroscopic resection of gross disease can be achieved, which operation to undertake depends on the individual patient’s tumour and functional status.7 This conclusion is reflected in the most recent clinical guidelines that were formulated by the 2012 International Mesothelioma Interest Group Congress (panel).10 Moreover, as techniques and perioperative management have improved, the mortality rates associated with these procedures—which were once prohibitively high—are now only 2·2—7% for EPP and 1—5% for P/D.279


Surgical recommendations discussed at the 2012 International Mesothelioma Interest Group Congress10

  • Surgical macroscopic complete resection and control of micrometastatic disease have an important role in the multimodality therapy of malignant pleural mesothelioma, as for other solid malignancies.
  • Surgical cytoreduction is indicated when macroscopic complete resection is deemed achievable.
  • The type of surgery (extrapleural pneumonectomy or pleurectomy/decortication) depends on clinical factors and on individual surgical judgment and expertise.
  • All patients with the diagnosis of malignant pleural mesothelioma should be initially assessed in a multidisciplinary setting, by medical oncology, radiation oncology, and surgical teams.
  • Clinical staging (lymph-node sampling, PET, and MRI) should be done before treatment.
  • The histological subtype should be identified by tissue biopsy before initiation of treatment.

Source: Lancet



Mannose-binding lectin and innate immunity in bronchiectasis.

Pathogenic microorganisms often thrive in the inflammatory milieu of the bronchiectatic airway where innate and adaptive defence mechanisms can be impaired. Although genetic defects of the adaptive immune system causing immunodeficiency syndromes are well characterised, genetic defects that impair the recognition of microbes by the innate immune system have only recently been identified.1 For example, polymorphisms in the gene for mannose-binding lectin (MBL), a receptor of the innate immune system that recognises microbial carbohydrates, can lead to deficiency of MBL and increased susceptibility to infection.

When the lungs are exposed to a new pathogen, the first line of defence is the innate immune system, which results in a swift and semi-specific response. Cells of the innate immune system, which include dendritic cells and macrophages, recognise highly conserved structures called pathogen-associated molecular patterns (PAMPs) that are shared by large groups of microorganisms. PAMPs are recognised by pattern-recognition receptors, which activate the cells of the innate immune system to rapidly attack and kill microbes.2

MBL is a soluble pattern-recognition receptor that is synthesised in the liver and is released into the systemic circulation as a component of the acute-phase response. It is not produced locally in the lungs and is thought to leak into the airways and alveoli from the systemic circulation, particularly in the presence of inflammation.3 MBL binds to various respiratory pathogens including Haemophilus influenzae and Pseudomonas aeruginosa, which are commonly identified in the airways of patients with bronchiectasis, and enhances the killing of these organisms by activation of the lectin complement pathway and by facilitating phagocytosis by opsonisation.4

In The Lancet Respiratory Medicine, James Chalmers and colleagues report a large, prospective study5 assessing the relation between MBL deficiency and clinical outcomes during a 4 year follow-up of patients with non-cystic fibrosis bronchiectasis. 55 (12%) of 470 patients with bronchiectasis had genotypes associated with MBL deficiency. These patients had more frequent exacerbations and were more likely to be chronically colonised with bacteria, particularly by P aeruginosa, than were patients with genotypes not associated with MBL deficiency. One strength of the study was the measurement of both MBL deficient genotypes and serum concentrations, which were strongly correlated. Serum MBL deficiency (<200 ng/mL) was also associated with increased exacerbation frequency.

The results of Chalmers and colleagues’ study5 are consistent with the findings from studies of patients with cystic fibrosis in which MBL deficiency has been associated with increased severity of disease. In patients with cystic fibrosis, MBL deficiency results in earlier acquisition of P aeruginosa, reduced pulmonary function, and increased mortality.6 However, a retrospective study7 of patients with non-cystic fibrosis bronchiectasis reported no association between low MBL concentrations and exacerbation frequency. Several conflicting results have also been published from studies8 assessing the association between low levels of MBL and acute exacerbations of chronic obstructive pulmonary disease.

What are the clinical implications of Chalmers and colleagues’ study? The study provides evidence that MBL deficiency is a new risk factor for infection and acute exacerbations in patients with non-cystic fibrosis bronchiectasis. Identification of patients at high risk of development of severe disease could direct clinicians to undertake more intensive management and follow-up of these patients with a view to reducing rates of hospital admission and mortality. Such stratification is increasingly relevant because of the growing range of treatments that is emerging for bronchiectasis. These treatments include long-term azithromycin, nebulised gentamicin, inhaled mannitol, inhaled dry powder ciprofloxacin, and nebulised liposomal ciprofloxacin. Recombinant human MBL might also become a treatment option, after it was reported in a phase 1 study9 to be safe, well tolerated, and able to restore activity of the lectin pathway of complement.

A standard definition of clinically significant MBL deficiency is not presently available but a diagnostic approach that incorporates both serum concentrations and genotyping seems sensible. Some patients with genotypes that are not associated with deficiency can still have very low MBL serum concentrations and, alternatively, serum concentrations can increase with the acute-phase response. One pragmatic approach analogous to that recommended by the American Thoracic Society and European Respiratory Society for α1-antitrypsin deficiency might be for clinicians to initially measure the serum concentration of MBL in patients with bronchiectasis. If the serum level is low, genotyping could then be undertaken. A cutoff of 200 ng/mL, as used in the study by Chalmers and colleagues, classified 19% of patients with bronchiectasis as MBL deficient. Better access to testing facilities and further studies are required to confirm the findings of the present study5before testing for MBL deficiency becomes routine practice in non-cystic fibrosis bronchiectasis. The present findings also raise some interesting questions for future research. MBL deficiency is relatively common in the general population and does not seem to predispose to an increased risk of infection in the absence of other predisposing factors. How do other predisposing factors interact with MBL deficiency to increase the risk of infection and cause severe disease or poor longitudinal outcomes in bronchiectasis? Could serial MBL concentrations in serum and sputum be used as markers for early detection of exacerbations or determination of the duration of antibiotic treatment? Does azithromycin interact with MBL to improve phagocytic activity in macrophages? Although some evidence suggests that azithromycin increases mannose receptor (a pattern-recognition receptor in the same family as MBL) expression and phagocytic activity in alveolar macrophages, the effect of azithromycin on MBL expression is unclear.

Source: lancet


Inhaled corticosteroids in severe COPD.


Guidelines and care pathways recommend inhaled corticosteroids (ICSs) over longacting bronchodilators in the treatment of patients with severe chronic obstructive pulmonary disease (COPD).12 A Cochrane review3 about the safety and efficacy of combined ICSs and longacting β2 agonists (LABAs) in one inhaler versus LABAs alone for COPD was published in September, 2012. Although the analysis was based on a large database (14 studies, 11 794 people), the conclusions were unclear about prevention of exacerbations, hospital admission, and mortality. Furthermore, moderate-quality evidence suggested an increased risk of pneumonia with ICS—LABA combinations. The authors concluded that more information about the relative benefits and adverse event rates of ICS—LABA combinations versus LABAs alone would be useful and that head-to-head comparisons are needed.3

Fluticasone furoate is a new ICS and vilanterol a new LABA. Both drugs are given once daily. A single inhaler combination of these drugs improved forced expiratory volume in 1 s (FEV1) after a short duration of treatment.4 In The Lancet Respiratory Medicine, Mark T Dransfield and colleagues5 report the results of the first long-term study comparing fluticasone furoate and vilanterol with vilanterol alone for major outcomes of COPD (ie, moderate or severe exacerbations). Two pooled multinational randomised controlled trials (study 1 and study 2) of 3255 patients with severe COPD ran for 52 weeks. Mean FEV1 after bronchodilators was 44—46% of predicted values. Three doses of fluticasone furoate were tested—50 μg, 100 μg, and 200 μg—all in combination with 25 μg vilanterol. The primary efficacy endpoint was the yearly rate of moderate or severe exacerbations. The authors defined moderate exacerbations as worsening symptoms of COPD (≥2 consecutive days) necessitating treatment with oral corticosteroids or antibiotics, or both; severe exacerbations were similar events that necessitated admission to hospital.

Dransfield and coworkers’ study5 is of great interest because it is, to my knowledge, the first investigating the combination of fluticasone furoate and vilanterol for major outcomes of COPD, and because it attempts to answer the queries that arose from the Cochrane review.3 Pneumonia occurrence was recorded and confirmed with chest radiographs. The study was very carefully done, although an independent expert panel did not assess severe adverse events, which might have led to underestimation of pneumonia risk.

The effect of fluticasone furoate and vilanterol compared with that of vilanterol alone is not large. In study 1, no significant difference in exacerbation rate was noted between the 200/25 μg fluticasone furoate/vilanterol group and the vilanterol only group. In study 2 and the prespecified pooled analysis, exacerbation rates were significantly lower in all fluticasone furoate/vilanterol groups than in the vilanterol only group. The frequency of only moderate exacerbations was significantly lower with fluticasone furoate and vilanterol than with vilanterol alone. Hospital admissions were uncommon in the studies and did not differ significantly between treatment groups. Thus, the additive effect of fluticasone furoate could not be shown—results that accord with those of the Cochrane review3 and reinforce the strength of evidence.

The safety of ICSs in COPD is a serious problem, which was underscored by Dransfield and colleagues’ results.5 Pneumonia (confirmed by radiography) and fractures were reported more frequently with fluticasone furoate and vilanterol than with vilanterol alone in studies 1 and 2 and the pooled analysis. Furthermore, severe cases of pneumonia were more frequent in the fluticasone furoate/vilanterol groups than in the vilanterol group. Eight pneumonia-related deaths were reported during treatment, seven participants taking 200 μg fluticasone furoate and one taking 100 μg fluticasone furoate. One case of fatal pneumonia was reported after treatment in the vilanterol only group. The authors raised concerns about the 200/25 μg dose. However, mortality was not increased in any study group, according with the results of Dong and colleagues.

Patients and clinicians should assess the potential benefits and risks of ICSs in severe COPD. For a practising physician, establishing which patients need ICSs (and which do not) is crucial. Randomised controlled studies published so far cannot answer this question because their results are based on means from large groups of patients. The phenotypic characteristics of patients who benefit from ICSs and those of patients prone to pneumonia would be of interest. Dransfield and coworkers’ study might enable an analysis of practical interest. It shows that the debate about ICSs in patients with severe COPD is not yet over, and suggests that a personalised medicine approach is needed for such patients.

Source: lancet




COPD treatment: time to change our algorithm?


For the past decade, clinicians have largely followed a set of similar algorithms for chronic obstructive pulmonary disease (COPD) therapy, initiating treatment with an inhaled longacting antimuscarinic (LAMA) and adding combination therapy with a longacting β agonist (LABA) plus an inhaled corticosteroid when symptom or exacerbation control is inadequate. This algorithm is also in accordance with the Global initiative for chronic Obstructive Lung Disease (GOLD) 2007 consensus statement.1 However, the GOLD 2013 consensus statement challenges clinicians to rethink this routine.2 A wide range of treatment options are proposed including LAMA/LABA dual therapy, which is recommended as a treatment alternative for group B (high symptoms/low risk), C (low symptoms/high risk), and D (high symptom/high risk) patients. However, few data have been available to support the efficacy of this combination therapy over single agent bronchodilator therapy. Good data already exist for the efficacy of LAMA monotherapy for symptom control and exacerbation reduction3 as well as for the efficacy of LABA monotherapy for symptom control,4 but scarce data have been available for whether dual agent therapy has additional benefit in terms of either symptom control or exacerbation reduction.

In The Lancet Respiratory Medicine, Jadwiga Wedzicha and colleagues5 present data from the SPARK study, a randomised, three-group, double-blind study in COPD comparing once-daily indacaterol plus glycopyrronium combination therapy (QVA149) versus glycopyrronium alone versus open-label tiotropium. The primary endpoint examined was superiority of QVA149 versus glycopyrronium in reducing the frequency of moderate to severe COPD exacerbations, with the comparison of QVA149 versus tiotropium as a major secondary endpoint. Inclusion criteria were post-bronchodilator forced expiratory volume in 1 s (FEV1) less than 50% and at least one exacerbation in the previous 12 months. This study showed a 12% reduction in the rate of moderate to severe exacerbations for QVA149 compared with glycopyrronium (rate ratio [RR] 0·88, 95% CI 0·77—0·99, p=0·038). The 10% reduction in moderate to severe exacerbations for QVA149 compared with tiotropium was not significant (RR 0·90, 95% CI 0·79—1·02, p=0·096). QVA149 also resulted in significantly higher trough FEV1 as compared to glycopyrronium (differences 70—80 mL, p<0·0001) and tiotropium (differences 60—80 mL, p<0·0001) and resulted in 8—9 unit improvements in St George’s Respiratory Questionnaire score (SGRQ) total score as opposed to 6 units with glycopyrronium and 5—6 units with tiotropium, both significant differences.

The real question is how these data should influence prescribing practices for COPD. These data support better lung function improvement, better symptom control, and greater exacerbation reduction with LAMA/LABA therapy as opposed to LAMA therapy alone in patients with severe to very severe disease. In reality, such patients are likely to be on some form of therapy before they progress to this level of disease severity. Hence for the patient already on LAMA therapy, the addition of a LABA, particularly if exacerbation reduction is a goal, as a next step in therapy is supported by these data.

These data must be interpreted in light of the fact that about 75% of patients were on concomitant inhaled corticosteroids, which has several implications. First, the magnitude of exacerbation reduction seen was 12%, which is arguably clinically significant but might have been attenuated owing to concomitant inhaled corticosteroid use. These results mirror the magnitude of reduction seen with tiotropium in the UPLIFT study,3 in which concomitant inhaled corticosteroid plus LABA therapy was allowed. Second, the high rates of concomitant inhaled corticosteroid use also mean that these data perhaps provide less support for the GOLD recommendation of LABA/LAMA as dual therapy for either groups C or D and perhaps provide greater support for triple therapy (addition of LABA to LAMA plus inhaled corticosteroids) for C and D patients.

In further thinking about how these data inform prescribing practices, one should also note that 22% of patients studied had two or more moderate or severe exacerbations in the previous year. Previous data suggest that group D patients who are judged to be at high risk by both FEV1 and exacerbation criteria are at even greater risk of moderate and severe exacerbations than are those meeting a single criterion, suggesting good efficacy in a relatively high risk population.6 On the other hand, another interesting finding of the study was that the greatest reduction was seen in mild exacerbations—15% with QVA149 compared with glycopyrronium and 16% compared with tiotropium—with mild exacerbations defined as an event with increase in symptoms but self-managed by the patient. Although exacerbation events requiring therapy are more frequently studied, the importance of untreated events should not be underestimated. Even events unreported to a health-care provider have been shown to be associated with significantly worse health status,7 which might explain the improvements in SGRQ score seen with QVA149 therapy.

Overall, these data support greater efficacy for dual bronchodilator therapy with QVA149 as compared with LAMA monotherapy. In view of the lack of data in the past, the use of combination LABA/LAMA therapy has not been embraced by medical practitioners for use in COPD, but these new data suggest dual therapy is an important therapeutic option when trying to maximise symptom improvement and exacerbation reduction.

Source: Lancet


Food production and obesity linked to climate change.


Horse meat sold as beef has made headlines and provoked consumer outrage in the UK, but the contribution of global food production—and particularly meat—to climate change is the larger scandal, according to experts who spoke to The Lancet Respiratory Medicine.

“Meat and dairy are a hotspot for ecological public health”, notes Timothy Lang (Centre for Food Policy, City University London, London, UK). “About half the world’s grain is fed to animals. The land and water use for such production systems are enormous. But this has created a situation where supposedly efficient modern agricultural systems have turned domestic animals as sources of cheap meat into direct competitors with humans for dominance in the ecological space.”

Although many people understand the threats that are posed to food systems by rising temperatures, extreme weather, and changing precipitation patterns, few seem to appreciate the degree to which human food production contributes to global climate change and the resulting health risks.

“It is bizarre that so many people in public health seem barely aware of food’s massive contribution to climate change”, remarks Lang. “This is not just unfortunate but downright irresponsible.”

An estimated 14% of greenhouse gas emissions come directly from agriculture (putting it on par with transportation emissions). Increasing transportation distances to market worsens food’s carbon footprint—a factor for which Lang coined the term “food miles.”

“A policy shift toward horticulture rather than animal-oriented agriculture is long overdue and is set to be a key challenge for the 21st century”, Lang believes. Public education campaigns to encourage people to eat less meat would seem to be the obvious direction for public health and environmental interventions meant to mitigate climate change. But public education is more easily advocated than implemented.

“In the past few years, several attempts to generate sustainable dietary advice for populations have come up against some big food-industry vested interests”, Lang says, citing recent controversies in Sweden, the UK, and Australia over proposed consumer advisories and nutritional guidelines. “Powerful interests will fight hard not to address the challenge of sustainability.”

Food production and agricultural and trade policies have been hijacked by a small number of large corporations in recent decades, agrees Wenonah Hauter (Food & Water Watch, Washington, DC, USA), whose father fled Oklahoma in the 1930s because of the so-called Dust Bowl—severe dust storms largely driven by agriculture.

In the USA, “20 large food processors own most brands on retail shelves”, notes Hauter. “Our political system is set up to allow companies to become larger and larger. During the Reagan administration, antitrust law was one of the main targets of the deregulatory agenda. They cut staff and enforcement budgets at regulatory agencies, and narrowed the definition of what constitutes an antitrust violation. Predictably, these companies became so large they’re able to dictate food and farm policy on everything from what pesticides we’re exposed to, to the way that food is made and labelled.”

US agriculture policy was further deregulated under the Clinton administration in the mid 1990s “to get in line with trade policy”, Hauter says. Deregulation of grain commodities during the 1990s saw increased corporate consolidation of corporate meat production, with the “factory farms” proportion of pork production, for example, rising from 30% in 1995 to 95% by 2005.

Under President Obama, efforts to curb junk food advertisements aimed at children yielded only “very weak voluntary guidelines”, Hauter says, which is testament to food industry lobbyists’ sway in Washington DC.

“Governments don’t govern; they follow”, cautions Lang. “Too often they are timid with regard to health and environment. The neoliberal perspective dominates: leave it to the consumer. But consumers are in the dark about the impact their food has on the planet, and the avalanche of cheap calories [in developed countries] acts as the model for what consumerism aspires to. But increasingly, scientists are aware that we need a new direction for food. We have to link human and environmental health.”

The interactions between abundant cheap calories, obesity, and the environment can generate complex feedback loops between climate, food, and epidemiology. The industrial production and global transportation of food contributes to global climate change, which affects agriculture through changes in precipitation and temperature, and extreme weather events. The effects will be felt unevenly around the planet, further impoverishing Africa’s agricultural base, for example. Overweight and obese people consume more food than others and rely disproportionately on travel by car, which together increases their carbon footprint to make obesity itself a serious global environmental problem, according to a 2009 study by scientists at the London School of Hygiene & Tropical Medicine.

The burden of respiratory disease is expected to increase with global temperatures, and the link between respiratory disorders, such as asthma and sleep apnoea, could be compounded by the environmental consequences of climate change. Extreme heat, air pollutants such as ozone and particulate matter, and increased production of plant and fungal allergens, will all conspire to drive up respiratory morbidity and mortality rates.

Early modelling studies predict that concentrations of pollen from common tree species such as oak and birch, and weeds such as the highly-allergenic ragweed, will increase by 20—30% by 2020, and will continue climbing for decades to follow, notes Leonard Bielory (Center for Environmental Prediction, Rutgers University, Springfield, NJ, USA). The US Environmental Protection Agency is funding research at Rutgers University to assess the effect of climate change on allergenic airway disease, says Bielory.

Respiratory syncytial virus infections are more common when temperatures are higher. Prolonged drought and increased airborne levels of particulate matter from wildfire smoke and dust—including the intercontinental movement of dust from growing expanses of African desert—are expected to exacerbate asthma and COPD symptoms.

Concentrations of ground-level ozone, a highly oxidative air pollutant, are expected to rise in some regions and drop in others, leading to increased rates of respiratory distress, exacerbated airway diseases such as asthma, and respiratory infection risks, adds Hans Orru (Department of Public Health, University of Tartu, Estonia). Predicted increases in ground-level ozone will hit central and southern Europe harder than northern Europe, which is likely to see declines in ozone, Orru says.

“There are a number of interactions between plant biology, which will certainly be affected by rising CO2 and increased temperature, and public health concerns. These interactions can run the gamut from aeroallergens to nutrition to pesticide use”, says Lewis H Ziska (Crop Systems and Global Change Laboratory, US Department of Agriculture, Beltsville, MD, USA). “There is initial evidence that all of these issues are already being affected.”

Recent and projected changes in atmospheric CO2 have been shown to change yields of plant food proteins, antioxidants, and omega-3 fatty acids, Ziska points out. “One key question we have is whether or not rising CO2 will also affect food allergies.” Ragweed pollen season has increased by as much as 13—27 days at higher latitudes since 1995, according to a 2011 study by Ziska, Bielory, and colleagues. Increased pollen seasons correspond to an increased number of frost-free days, Bielory notes.

Another key question is whether or not plant pollen might become more allergenic with changing temperatures or CO2 levels. The effects of air pollutants on respiratory health can be compounded by the presence of respiratory allergens, Ziska notes. Pollen sticks to larger particulate matter associated, for example, with diesel fumes. “The particulate matter can act as a platform that attracts pollen and drives it further into the lungs”, Ziska explains. Sensitisation to common seasonal allergens has doubled over the past 20 years along with symptoms, Bielory has found.

In addition to airborne allergens, the effect of climate change on plant communities might lead to larger populations of disease vectors such as mosquitoes, whose larvae can feed on pollen.

AJ McMichael (National Centre for Epidemiology and Population Health, Australian National University, ACT, Australia) and others believe that major civilisational shifts, resulting in starvation, warfare, migration, and revolution, have accompanied abrupt climatic change in the past. A recent report even links droughts in wheat-producing regions of the globe with the Arab Spring uprisings in countries that are among the largest wheat importers.

Climate change will unveil complex interactions between plants and human physiology, Ziska concludes. “We are getting a sense of what some of those interactions are, and how significant they are, but we have a great deal more yet to do”. Untangling these interactions will be a major interdisciplinary endeavour.

Source: lancet


Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial.


EGFR overexpression occurs in 27—55% of oesophagogastric adenocarcinomas, and correlates with poor prognosis. We aimed to assess addition of the anti-EGFR antibody panitumumab to epirubicin, oxaliplatin, and capecitabine (EOC) in patients with advanced oesophagogastric adenocarcinoma.


In this randomised, open-label phase 3 trial (REAL3), we enrolled patients with untreated, metastatic, or locally advanced oesophagogastric adenocarcinoma at 63 centres (tertiary referral centres, teaching hospitals, and district general hospitals) in the UK. Eligible patients were randomly allocated (1:1) to receive up to eight 21-day cycles of open-label EOC (epirubicin 50 mg/m2 and oxaliplatin 130 mg/m2 on day 1 and capecitabine 1250 mg/m2 per day on days 1—21) or modified-dose EOC plus panitumumab (mEOC+P; epirubicin 50 mg/m2 and oxaliplatin 100 mg/m2 on day 1, capecitabine 1000 mg/m2 per day on days 1—21, and panitumumab 9 mg/kg on day 1). Randomisation was blocked and stratified for centre region, extent of disease, and performance status. The primary endpoint was overall survival in the intention-to-treat population. We assessed safety in all patients who received at least one dose of study drug. After a preplanned independent data monitoring committee review in October, 2011, trial recruitment was halted and panitumumab withdrawn. Data for patients on treatment were censored at this timepoint. This study is registered with, number NCT00824785.


Between June 2, 2008, and Oct 17, 2011, we enrolled 553 eligible patients. Median overall survival in 275 patients allocated EOC was 11·3 months (95% CI 9·6—13·0) compared with 8·8 months (7·7—9·8) in 278 patients allocated mEOC+P (hazard ratio [HR] 1·37, 95% CI 1·07—1·76; p=0·013). mEOC+P was associated with increased incidence of grade 3—4 diarrhoea (48 [17%] of 276 patients allocated mEOC+P vs 29 [11%] of 266 patients allocated EOC), rash (29 [11%] vs two [1%]), mucositis (14 [5%] vs none), and hypomagnesaemia (13 [5%] vs none) but reduced incidence of haematological toxicity (grade ≥3 neutropenia 35 [13%] vs 74 [28%]).


Addition of panitumumab to EOC chemotherapy does not increase overall survival and cannot be recommended for use in an unselected population with advanced oesophagogastric adenocarcinoma.


The REAL3 trial is one of two concurrent randomised phase 3 trials (the other being the EXPAND trial15) assessing the addition of anti-EGFR monoclonal antibodies to chemotherapy in first-line oesophagogastric cancer. Based on the findings of REAL3, use of panitumumab in combination with EOC cannot be recommended in an unselected population with advanced oesophagogastric adenocarcinoma, and was associated with inferior overall survival and PFS. Notably, this detrimental outcome in the experimental group was not predicted by the phase 2 endpoint of response rate (overall response rate 52% with mEOC+P). This trial does, however, confirm the efficacy of the EOC control group in this setting, with median overall survival and PFS results that are consistent with those previously reported in REAL2 (11·2 months for overall survival and 7·0 months for PFS).3

The poor outcome associated with mEOC+P in this trial did not seem to be attributable to increased treatment-related deaths, and therefore other potential explanations for our findings need to be considered. First, as reported previously,12combination of panitumumab with full-dose EOC in the initial stages of the trial was associated with unacceptably high rates of grade 3 diarrhoea (four of the first five patients by cycle four). Therefore, we had to reduce the starting doses of oxaliplatin (by 23%) and capecitabine (by 20%) in the experimental group. Although these changes undoubtedly reduced the frequency of grade 3—4 diarrhoea with mEOC+P (17% in phase 3 population), they also served to reduce the dose intensity of chemotherapy, which is reflected in the reduced incidence of grade 3—4 neutropenia and peripheral neuropathy noted in the mEOC+P group. Additionally, the dose intensity data show a reduced proportion of patients achieving at least 80% of the planned capecitabine dose in the experimental group, suggesting that mEOC+P was still slightly more difficult to deliver than standard EOC.

Second, a negative interaction might have occurred between panitumumab and one or more of the EOC components. Evidence in the setting of colorectal cancer suggests that the chemotherapy partner for anti-EGFR therapy might be an important determinant of treatment efficacy, with oxaliplatin-containing regimens yielding inconsistent results. The OPUS16and PRIME11 studies provide evidence of improved outcomes with the addition of cetuximab and panitumumab respectively, whereas no benefit was associated with the addition of cetuximab in the COIN17 and NORDIC VII18 studies in the same setting. Recent cell-line data also suggest that greater synergy might exist between anti-EGFR therapy and irinotecan than with oxaliplatin.19 Additionally, the COIN trial17 results suggest that there might be a differential benefit from cetuximab dependent on the fluoropyrimidine partner, with patients receiving oxaliplatin plus fluorouracil seemingly deriving increased benefit compared with those treated with oxaliplatin plus capecitabine. At present, the significance of these potential interactions is unknown, and has not been assessed in the setting of oesophagogastric cancer.

Third, our findings might have been affected because we assessed panitumumab therapy in a molecularly unselected population. During the years since the inception of the REAL3 trial, several studies have advanced our understanding of the EGFR signalling pathway and its role in oesophagogastric adenocarcinoma. Hot-spot mutations in key oncogenic drivers such as KRAS (common in colorectal cancer) and BRAF (common in malignant melanoma) are now known to be infrequent molecular events in oesophagogastric adenocarcinoma. Indeed, the 5·7% frequency of KRAS mutation in our population is in keeping with the 3—10% reported in other studies,20—22 and we did not note any BRAF mutations in 167 tumour samples tested. By contrast, gene copy number alterations (amplifications and deletions) seem to be a relatively frequent finding in oesophagogastric adenocarcinoma and are more likely to represent the key molecular alterations driving carcinogenesis. Two recent series2324 of detailed genomic analyses in oesophagogastric adenocarcinoma reported that about 37% of tumours harbour copy number aberrations in genes that are deemed to be targetable, including KRASEGFRHER2, and MET. Randomised clinical trials are therefore needed to establish whether targeting of these oncogenic signal transduction pathways can meaningfully improve outcomes for patients.

In preclinical studies, cetuximab can decrease EGFR pathway signalling via reduced phosphorylation of EGFR and AKT in oesophagogastric cancer cell lines.25 In combination with chemotherapy, cetuximab results in synergistic inhibition of cell proliferation and enhanced apoptosis.25—27 In hypoxic gastric cancer cell lines the addition of anti-EGFR therapy reversed oxaliplatin resistance.26 Additionally, a synergistic antitumour effect of combined cetuximab and S-1 was apparent in gastric cancer cell lines overexpressing EGFR.2527 In colorectal cancer, somatic mutations in codon 12, 13, or 61 of the KRASoncogene confer resistance to panitumumab therapy.1128 MET amplification with or without KRAS mutations might be associated with resistance to cetuximab therapy in gastric cancer cell lines;29 however, no validated predictive biomarkers for this setting exist.

Unfortunately, despite preclinical data suggesting a role for anti-EGFR therapy in the treatment of oesophagogastric adenocarcinoma, the REAL3 trial findings are supported by two other phase 3 trials assessing anti-EGFR therapy in this disease setting. The EXPAND trial15 assessed the addition of cetuximab to a cisplatin-capecitabine doublet in 904 patients with previously untreated adenocarcinoma of the stomach and gastro-oesophageal junction, and did not meet its primary endpoint of improved PFS (HR 1·09, 95% CI 0·92—1·29, p=0·32).15 EXPAND also noted no improvement with the addition of cetuximab in either overall survival (HR 1·00, 95% CI 0·87—1·17, p=0·95) or overall response rate (30% in the experimental group vs 29% for controls). The COG trial30 assessed the anti-EGFR tyrosine-kinase inhibitor gefitinib compared with placebo in the second-line treatment of 450 patients with oesophageal and type I—II gastro-oesophageal junction cancers. This trial also did not meet its primary endpoint, with no improvement in overall survival (HR 0·90, p=0·285). However, improvements in PFS (HR 0·795, p=0·017) and disease control at 8 weeks (25·5% in the experimental group vs 16·0% in controls, p=0·014) were noted, suggesting some activity of gefitinib in a small undefined subset of patients.

Taken together, these relatively consistent findings suggest that the EGFR pathway is unlikely to represent an important therapeutic target in most patients with oesophagogastric cancer (panel). The presented biomarker analyses accompanying the REAL3 trial are restricted by small patient numbers and low rates of tested mutations. However, this work is ongoing in the full trial dataset and these translational analyses represent a unique opportunity to further assess the molecular biology of advanced oesophagogastric adenocarcinoma within a randomised trial setting. Techniques such as gene-expression profiling and next-generation sequencing might help to provide further information regarding the driver genetic events in this complex disease. Furthermore, the evaluation of genetic aberrations in pathways linked to EGFR signalling could still offer the prospect of identification of a low-frequency biomarker that identifies a subpopulation of patients benefiting from anti-EGFR targeted therapy in this setting.

Source: lancet

Protein phosphatase 2A: a target for anticancer therapy.

Protein phosphatase 2A (PP2A), one of the main serine—threonine phosphatases in mammalian cells, maintains cell homoeostasis by counteracting most of the kinase-driven intracellular signalling pathways. Unrestrained activation of oncogenic kinases together with inhibition of tumour suppressors is often required for development of cancer. PP2A has been shown to be genetically altered or functionally inactivated in many solid cancers and leukaemias, and is therefore a tumour suppressor. For example, the phosphatase activity of PP2A is suppressed in chronic myeloid leukaemia and other malignancies characterised by aberrant activity of oncogenic kinases. Preclinical studies show that pharmacological restoration of PP2A tumour-suppressor activity by PP2A-activating drugs (eg, FTY720) effectively antagonises cancer development and progression. Here, we discuss PP2A as a druggable tumour suppressor in view of the possible introduction of PP2A-activating drugs into anticancer therapeutic protocols.

Source: lancet


New options for second-line therapy of advanced renal cancer.


Several drugs targeting VEGF or mTOR pathways have been approved for treatment of advanced renal-cell carcinoma because of improvements noted in progression-free survival (PFS) in phase 3 trials.1 Validation of prognostic models showed that treatment with such drugs can lead to a median overall survival of around 43 months for patients in favourable risk categories and 23 months for patients in intermediate risk categories.2 With few exceptions, patients on first-line therapy progress and proceed to need one or more subsequent lines of targeted therapy. In a population-based study,3 patients in a favourable risk group had progression on first-line VEGF-targeted therapy after a median of 16·6 months (compared with 15 months for patients in an intermediate risk group) and progression after 6·2 months on second-line targeted therapy (5·5 months for intermediate risk). Two phase 3 trials45 assessed outcomes after failure of a previous VEGF-targeted therapy to establish evidence for the mTOR-inhibitor everolimus and the selective inhibitor of VEGF receptors 1—3, axitinib. The AXIS trial5 is the only study that directly compared two active compounds (axitinib vs sorafenib) after failure of an approved first-line regimen. In AXIS, more than a third of patients had received cytokines and over half had received sunitinib as first-line therapy. Axitinib led to an improvement in median PFS compared with sorafenib in the intention-to-treat analysis. However, the difference in PFS for patients after sunitinib treatment based on investigator and independent review committee assessments was only slight. Data for overall survival, a secondary endpoint, were immature before the first report was published in 2011. Because guidelines and clinical practice favour targeted therapy in preference to cytokines as first-line treatment,1 axitinib is regarded as a treatment option for second-line therapy of advanced renal-cell carcinoma.5

In The Lancet Oncology, Robert Motzer and colleagues6 now report mature overall survival data for the AXIS trial. Such an analysis is important because crossover between the two study arms was not allowed. No significant differences in overall survival were noted between patients in both treatment arms who received the same first-line regimen (median overall survival 20·1 months [95% CI 16·7—23·4] with axitinib vs 19·2 months [17·5—22·3] with sorafenib; hazard ratio 0·969, 95% CI 0·800—1·174, p=0·3744). More than half the patients in each arm continued with a third-line treatment after progression on study drug and treatment after progression was allowed. This design confounded overall survival results and raises questions as to whether PFS is meaningful in this setting.7 Third-line therapy partly explains the long time interval noted between progression on second-line treatment and overall survival. However, inclusion of patients with a less aggressive tumour biology might have contributed to this outcome. Only a third of patients in the AXIS trial were Memorial Sloan Kettering Cancer Center (MSKCC) poor risk at entry,5 suggesting that individuals with rapid deterioration of performance or accelerated progression during first-line therapy are less likely to enter trials than are patients with more favourable risk profiles.

For patients previously treated with sunitinib in Motzer and colleagues’ study,6 median time on first-line therapy was about 10 months, with a median overall survival for all risk groups of 15·2 months (95% CI 12·8—18·3) for axitinib and 16·5 months (13·7—19·2) for sorafenib. Patients who received cytokines had first-line therapy for about 6 months and a median overall survival of 29·4 months (24·5—not assessable) for axitinib and 27·8 months (23·1—34·5) for sorafenib. After correction for the different length of first-line therapies, overall survival seemed to be increased by about 7—9 months in patients who had cytokines before VEGF-targeted therapy. Resistance to previous VEGF-targeted therapy, which might not be apparent in patients previously untreated with such an approach, cannot fully explain this difference. Motzer and colleagues noted a putative association of overall survival with length of previous sunitinib treatment for both axitinib and sorafenib, although there was substantial overlap in the 95% CIs.6 A retrospective Database Consortium analysis of 464 patients who had received two lines of VEGF-targeted therapies reported no correlation between first-line PFS and second-line PFS.8 Rather, a significant difference in multivariate analysis of baseline prognostic factors in favour of cytokine versus sunitinib pretreatment (HR 0·503, 95% CI 0·395—0·641; p<0·0001) suggested that patients with less advanced disease were most likely to start treatment with cytokines.6 However, information about the distribution of prognostic factors between patients who were pretreated with cytokines and sunitinib, which could have important implications for treatment sequences, is not provided in Motzer and colleagues’ study.

Data from trials and population-based analyses suggest that a ceiling has almost been reached in terms of outcome with present targeted therapies and prognosis that relies on models based on clinical factors.2 The mature AXIS data add axitinib to the choices for second-line treatment with similar outcome and different toxicity profiles.4—6 Despite prognostic factors assessed in the updated analysis and a correlation of development of hypertension during axitinib and sorafenib treatment with overall survival, the choice for a second-line drug or even treatment beyond progression at failure of first-line treatment remains an educated guess. The outcome of this study proves once again that renal-cell carcinoma is a heterogenous cancer9 that needs further research into predictive biomarkers to tailor treatment choices.

Source: Lancet


Mesothelioma: closer to the target?



Patients and families of patients with mesothelioma do not ask for much. They have no time to waste on therapies that have proven useless for extending survival when confronted with the incredibly small portfolio of efficacious treatment options in this disease. For this reason, Wieneke Buikhuisen and colleagues’ long awaited, superbly designed and executed switch maintenance trial with thalidomide1 is a landmark achievement in mesothelioma, despite the fact that it failed to show improvement in time to progression compared with best supportive care (median time to progression 3·6 months in the thalidomide group vs 3·5 months in the active supportive care group; hazard ratio [HR] 0·95, 95% CI 0·73—1·20, p=0·72). This 5 year randomised trial in 222 patients represents an international collaboration and involved a novel approach built on previous data, thoughtful stratification of the two cohorts, central reading of imaging, and an attempt to correlate contemporary biomarkers and inflammatory or angiogenic-related molecules with time to progression and survival.

So what are the implications that no benefit was reported for yet another attempt to control the angiogenic pathway in mesothelioma? The outcome means that despite our greatest efforts to understand the biology of this disease, and to target promising pathways that seem to contribute to mesothelioma progression, we have no idea which of these pathways is most important, and specifically in which patients we should target that pathway. Within the data presented in this trial there are hints for future work, albeit limited by lack of power. Interleukin 6 seems to be prognostic in a small subset of patients, and non-epithelial histology classically has a worse prognosis than epithelial. Careful scrutiny of the data reveals that the hazard ratio for use of thalidomide seems to favour improved time to progression in individuals with raised interleukin 6 (HR 0·7, 95% CI 0·3—1·4) and non-epithelial histology (0·8, 95% CI 0·3—2·2), which is the very group that we would like to see results in. Although the statistical chance that this is a real finding might be small, the point is that thalidomide, like other new drugs, must be used only in patients for whom a benefit will be seen, and until we are able to match predictive markers with carefully done randomised trials, we could be harming some patients. Buikhuisen and colleagues point this out in their analyses, which showed shorter median overall survival in the thalidomide group (10·6 months) than in the active supportive care group (12·9 months), although this difference was not significant (HR 1·2, 95% CI 0·9—1·6, p=0·21). Certainly logic would dictate that it is high time to use specific agents to hit specific targets in mesothelioma.

But do we have any reasonably specific targets for mesothelioma? Many of the ongoing trials, unlike thalidomide therapy, are based on targeting a molecule that seems to be specific to the disease. Unfortunately, however, despite overexpression of EGFR in mesothelioma,23 most studies with the exception of two4—6 have not described the common mutations seen in non-small-cell lung cancer, and no efficacy has been noted for gefitinib7 or erlotinib.8 By contrast, the glycoprotein mesothelin9 is overexpressed in mesothelioma as well as selected other tumours, and is being targeted for therapy with recombinant immunotoxins10 or monoclonal antibodies.11 Both therapies have had encouraging preliminary responses in combination with pemetrexed and cisplatin. Finally, WT1 peptide vaccination has been shown to elicit immune responses in mesothelioma patients who overexpress WT1,12 and is the basis for an ongoing post-chemotherapy vaccination trial (NCT01265433).

So why do we struggle and why is the pace of success in mesothelioma so slow? In this orphan disease, as illustrated by this trial, patient accrual takes a long time, and when we do accrue patients, we really must study the disease using a coordinated, multiplatform, and novel technology based approach. We need to have sufficient archives of longitudinally collected serum, plasma, mononuclear cells, and paraffin blocks so that we can define genomic, proteomic, microRNA, or metabolomic differences between responders and non-responders for a given therapy. This discussion leads into another emerging issue, which is our interpretation of response to therapy considering the complex geometry of the abdomen and the pleura. We need trials that are large enough to allow accurate definitions of response, possibly using tumour volumes13,14 or metabolic volumes.15

There is no question that we need more randomised trials in mesothelioma to help us to discard useless therapies and pursue promising ones; however, we need to pick up the pace for all inclusive phase 2 ventures that have enough power not only to define promising efficacy to move to phase 3 but also to define molecular or biochemical reasons for this efficacy, as well as to validate more quantitative ways of recording responses. International efforts must therefore not only plan for central interpretation of clinical endpoints, but also prepare for validation of novel discoveries from the archives of such trials. Obviously, funding for these efforts is crucial, but without proper insightful and forward-looking trial planning, funding support will certainly be as difficult as improving survival for these patients.

Source: Lancet


Arm lymphoedema after breast cancer.


Breast-cancer-related lymphoedema is a substantial problem in women after they have undergone breast cancer treatment. Despite the introduction of breast-conserving surgery and minimal lymphatic intervention (eg, sentinel-lymph-node biopsy [SLNB]), incidence rates remain disappointingly high. In The Lancet Oncology, Tracey DiSipio and colleagues1 report the findings of their systematic review and meta-analysis in which they shown that roughly one in five women with breast cancer will develop arm lymphoedema.1 The incidence was four times higher in women undergoing axillary lymph-node dissection compared with those who received sentinel-lymph-node biopsy.

Lymphoedema is the accumulation of lymph in the interstitial spaces caused by the failure of the lymph-conducting system (lymph and lymph glands) to absorb or transport lymph back to the blood circulation.2 The drainage basin of the axillary lymph glands is the ipsilateral breast, upper quadrant of the trunk, and the upper limb. Consequently, any disruption to lymph flow through the axilla can result in lymphoedema in any part of the drainage basin. With breast conservation rather than mastectomy as standard treatment, breast lymphoedema has become much more of a clinical problem but has received much less research attention. Because breast lymphoedema can occur without arm swelling, the overall incidence of breast cancer-related lymphoedema within the forequarter is probably higher than data for arm swelling alone suggest.

The pathophysiology of breast cancer-related lymphoedema is complicated. Although interference with lymph drainage routes is fundamental to its development, the exact mechanisms leading to swelling are poorly understood. In view of the consistency of treatment protocols for breast cancer, some clinical questions remain unanswered. Why do most women not develop breast cancer-related lymphoedema? Why can such lymphoedema develop either immediately or many years after having breast cancer? Why is the distribution of swelling in the arm non-uniform (eg, a patients’ forearm can be swollen but not their hand)? If lymphatic obstruction post-surgery is the cause, then the whole upper limb could be expected to be affected, but this is often not the case.

Findings from studies done since 2009 have shown that after axillary surgery and before the onset of oedema, women who later develop breast cancer-related lymphoedema have higher lymph flows (and not lower as one might expect) than women who do not develop lyphoedema.3 Lymph flow is also increased in the contralateral arm, indicating axillary surgery has a systemic not just a regional effect.34 Furthermore, lymphatic pump failure develops in established breast cancer-related lymphoedema.5 One hypothesis is that an as-yet-unidentified subgroup of women with higher lymph flows develop such lymphoedema because of the chronically increased lymph load working against increased lymphatic outflow resistance, which then causes lymphatic pump failure.6

DiSipio and colleagues identified obesity and more extensive surgery as risk factors lent support by strong evidence. Whereas more extensive surgery as a prognostic factor is understandable, the relation between obesity and arm lymphoedema is more complex. A functional link has emerged between lymphatic malfunction and the pathogenesis of obesity.7Furthermore, much of the swelling that occurs with arm lymphoedema is fat not fluid, which has led to liposuction as a treatment for breast cancer-related lymphoedema when first-line decongestive lymphatic therapy (manual lymph drainage, compression and exercises) has fully resolved the fluid component.8

The lymphatic system is the most common route for cancer spread and, in theory, blocking that route would do much to reduce cancer mortality. The problem has been that for centuries the lymphatic system has been the subject of gross neglect, mainly because of the absence of investigations to realise its importance to human pathology and disease. But that shortfall is changing, with the discovery of new lymphatic genes and molecular proteins.7 However, until a new drug that can modulate lymph flow or lymphatic function is developed, the lymphatic system, and in particular lymphoedema, will remain under-recognised by most practising oncologists. Attempts at improving lymph drainage by surgical means has had a resurgence with the development of lymphaticovenular anastomoses9 and lymph-node transfer operations.10 Lymph-node transfer combined with VEGF-C to stimulate lymphangiogenesis is entering phase 1 trials.7 Ideally, such developments will generate greater awareness and interest in lymphoedema, which remains one of the most common and distressing consequences of breast cancer and its treatment.

Source: Lancet