Study shows white blood cell boosting drugs safe during chemo-radiotherapy of lung cancer

 A late breaking subanalysis of the phase III CONVERT trial presented at the European Lung Cancer Conference (ELCC) shows that white blood cell boosting drugs are safe during concurrent chemo-radiotherapy of small cell lung cancer (SCLC).

“The optimal treatment for limited-stage SCLC is concurrent chemo-radiotherapy,” said lead author Dr Fabio Gomes, a medical oncologist at the Christie NHS Foundation Trust, Manchester, UK. “The efficacy of this intensive treatment is balanced by more toxicity, mainly haematological but also oesophageal and pulmonary. Meaning this is not a treatment to be considered for every patient and many more will struggle to stay on track with the planned treatment”.

Granulocyte colony-stimulating factors (G-CSFs) are commonly used as a supportive measure to boost the survival, proliferation and differentiation of neutrophils. The expected neutropenia is less severe and patients recover more quickly, reducing their risk for infectious complications. However, its use during concurrent chemo-radiotherapy in SCLC is controversial and the American Society of Clinical Oncology (ASCO) recommends against its routine use.This is due to a randomised trial with 215 eligible patients performed between 1989 and 1991, which showed a significant increase in severe thrombocytopenia, severe anaemia, pulmonary complications and toxic deaths when granulocyte-macrophage CSFs (GM-CSFs) were used during concurrent chemo-radiotherapy.

Gomes said: “There have been two major changes since this trial was published in 1995 which may affect the safety of CSF in this context. First, the trial tested GM-CSFs which act on more than one blood cell lineage and are not commonly used nowadays. Instead we use G-CSFs, which are more specific and aim for the neutrophil lineage only. Second, modern radiotherapy techniques have evolved significantly since then and are more precise, which reduces the risks of toxicity.”

The phase III CONVERT trial enrolled 547 patients with limited-stage SCLC for concurrent chemo-radiotherapy who were randomised to once-daily or twice-daily radiotherapy. There was no difference in overall survival between the two groups.

The trial protocol allowed the use of G-CSF, and around 40% of patients received it at some point during the treatment. For the analysis presented today, the researchers compared the toxicities and outcomes between patients who received G-CSF during concurrent chemo-radiotherapy and those who did not.

They confirmed that the chance of severe thrombocytopenia or anaemia during treatment almost doubled in patients given G-CSF to around 30% and 20%, respectively, however these were lower than previously reported. That was followed by a significantly higher use of further supportive measures such as platelets and blood transfusions. However, there was no difference in the incidence of pulmonary complications or in survival.

Gomes said: “G-CSF had no significant negative impact on the outcomes of these patients, which is a very comforting result. The higher haematological toxicity was balanced by an appropriate supportive care throughout treatment.”

He continued: “We can conclude from this analysis that the use of G-CSF during thoracic radiotherapy is safe and should support patients to receive the full planned course of concurrent chemo-radiotherapy and achieve the best possible benefit. These findings should give clinicians the confidence to use G-CSF when needed in this context. We aim to publish a complete analysis later this year which may hopefully help change the current guidelines.”

Commenting on the findings, Dr Stefan Zimmermann, Senior Consultant, Medical Oncology Department, HFR – Hôpital Cantonal, Fribourg, Switzerland, said: “Oncologists do need G-CSF to mitigate neutropenia and increase chemotherapy delivery and compliance, but want the beneficial effect of timely concurrent therapy to outweigh the toxic risks.”

“In this analysis, the use of G-CSF did not result in an increased risk of pneumonitis, but the incidence of severe thrombocytopenia is a concern,” he continued. “The use of G-CSF was not detrimental to progression-free survival or overall survival. We can conclude that primary or secondary prophylaxis of febrile neutropenia with G-CSF is justified, but patients at higher risk for thrombocytopenia should be treated with caution.”

 he reference event in Europe for professionals treating lung cancers. It is organised by the European Society for Medical Oncology and the International Association for the Study of Lung Cancer in partnership with ESTRO and ETOP.

Thousands of melanoma patients in Europe have no access to new life saving drugs

  Over 5000 patients with metastatic melanoma in Europe are denied access to new, life saving drugs every year, according to a survey presented at the ESMO 2016 Congress in Copenhagen¹.

Metastatic melanoma is an aggressive and deadly skin cancer. With innovative targeted therapy and immunotherapy, patients can survive for many years. Unfortunately new therapies are expensive so, according to a survey conducted by Dr Lidija Kandolf-Sekulovic, over 5000 patients with metastatic melanoma in Europe have no access to these drugs.

“Before 2011 there were no effective treatment options for metastatic melanoma patients, but that has changed tremendously in the last 5 years. We now have medicines which can prolong overall survival of these patients to more than 18 months and, in some patients, durable responses lasting up to 10 years have been reported. However, access to these medicines is limited and patients and physicians are facing increasing difficulties to obtain them. This is especially the case for Eastern and South Eastern European countries, where a majority of patients are still treated with palliative chemotherapy that does not prolong overall survival,” said Kandolf-Sekulovic.

The survey showed that in Western Europe 70% of patients were treated with innovative medicines, while in Eastern Europe less than 10% of patients had access to the latest treatment recommended by current European Guidelines (ESMO, EORTC/EADO) (2).

The study found that the BRAFi+MEKi combination (one of the first-line treatments besides immunotherapy for BRAF mutated metastatic melanoma) was registered in 75% of Western European countries and fully reimbursed in 58%. In Eastern Europe, the treatment was registered in 42% of countries and only reimbursed in 18%, with time consuming administrative work needed to obtain the medicines in all cases.

The survey estimated that around 19.250 metastatic melanoma patients are treated every year in Europe and nearly 7.450 (39.7%) in Eastern and South-Eastern Europe. Of these patients, 5.128 (69%) do not have the access to first-line therapy according to European guidelines. Overall, it can be estimated that in Europe 5.228/19.250 (27%), i.e. almost one third of all metastatic melanoma patients, do not have access to innovative medicines.

In Europe, about 1 in every 100 people will develop melanoma at some point in their life, but important variations exist from one country to another. This number is increasing in almost all European countries. Melanoma is slightly more frequent in females than in males and more frequent in Switzerland, the Netherlands and the Scandinavian countries (Norway, Sweden and Denmark), where about 20 out of 100,000 people are diagnosed each year. From 1999-2012 there has been a 78% recorded increase in Germany. Similar increases were recorded also in the United States, Australia, Norway and Denmark, as well as countries in South-Eastern Europe.

Kandolf-Sekulovic explained: “Our study raises ethical questions on the inequalities that affect survival based on the country of residence in Europe. It is not new that disparities in healthcare can lead to disparities in overall survival of patients, but these disparities are becoming even sharper for patients with chemotherapy resistant metastatic melanoma in whom durable responses lasting for years can be seen in up to 20% of patients if treated with innovative medicines. In European healthcare systems that declare universal access to healthcare, these inequalities must be overcome.”

Dr Alexander Eniu, Chair of the ESMO Global Policy Committee, said: “This study confirms what ESMO has highlighted in the past: access to the best treatment according to evidence based clinical guidelines such as ESMO’s, is not equal across Europe. ESMO advocates for equal access to treatment and care, which is the fundamental right of any patient.  Despite the encouraging rate of new medicine development, there are still unacceptable inequalities in the availability and accessibility of new and effective cancer medications across Europe.”

 “The present study focuses on melanoma but the ESMO-led European Consortium Study on the availability and accessibility of anti-neoplastic medicines across Europe (3) found that the same was true for other types of cancer, especially rare cancers, in countries with lower economic levels.  It is important to continue to provide health authorities with data, and to carry on calling attention to the difficulties patients with incurable diseases are facing, in the hope that equal access will soon be a reality, at least in Europe,” said Eniu.

“This every day situation which is source of a large frustration for metastatic melanoma patients, their families and physicians, needs to be adressed urgently by all stakeholders. We need harmonisation of reimbursement procedures throughout Europe, adjusted programmes for early access to innovative medicines in countries with delayed reimbursement and sustainable pricing for these life saving drugs,” concluded Kandolf-Sekulovic.

Comfy Mice Lead to Better Science: Are Cold Mice Affecting Drug Testing?

 Nine out of 10 drugs successfully tested in mice and other animal models ultimately fail to work in people, and one reason may be traced back to a common fact of life for laboratory mice: they're cold, according to a researcher at the Stanford University School of Medicine.

Laboratory mice, who account for the vast majority of animal research subjects, are routinely housed in chilly conditions, which may affect their well-being as well as the outcome of research studies, said Joseph Garner, PhD, associate professor of comparative medicine.
"If you want to design a drug that will help a patient in the hospital, you cannot reasonably do that in animals that are cold-stressed and are compensating with an elevated metabolic rate," Garner said. "This will change all aspects of their physiology -- such as how fast the liver breaks down a drug -- which can't help but increase the chance that a drug will behave differently in mice and in humans."
In a new study, Garner and his colleagues report finding an easy solution to the problem: Simply provide the animals with the proper materials, and they'll build a cozy nest that allows them to naturally regulate their temperatures to a comfortable level. These thermally content mice would be more physiologically comparable to humans and thus might serve as more meaningful research subjects, Garner said.
"Why not let them do what they do in the wild, which is build nests? Mice can happily infest a meat freezer, with temperatures far below zero, but they survive and breed because they build these wonderful nests," he said.
The study, part of nearly seven years of work with mouse nesting behavior, is the first to "ask" mice to rate the value of nesting material in terms of temperature savings, which is an important first step in setting standards for nesting material, said Garner, whose work has focused on the well-being of the mouse. He is the senior author of the study, which was published online March 30 in PLoS ONE.
Mice, which Garner calls "one of the most fantastic animals on Earth," have evolved in the same environment as humans for thousands of years, making them remarkably adaptable, able to live virtually anywhere. For that reason, they make excellent research subjects, with hundreds of millions of them populating laboratories around the world.
Given the option, mice gravitate to temperatures of between 30 and 32 degrees Celsius (the equivalent of about 86 and 90 degrees Fahrenheit). But based on federal regulations, U.S. research laboratories are routinely kept on the cold side -- between 20 to 24 degrees C. There can be advantages to these cold temperatures. For instance, mice have aggressive tendencies that are suppressed in cooler climes. Female mice also lactate better in cooler temperatures, though their pups don't do as well in the cold.
When kept in temperatures toward the low end of this scale -- between about 18 and 20 degrees C (64-68 degrees F) -- the mice begin to show changes in immune function and their growth may be retarded. "So we're housing them right at that threshold," Garner said. "That means the mice may be compromised physiologically, potentially affecting research results."
Simply raising the temperature in the lab isn't an option, not least because the mice would then become unmanageably aggressive, he said. Rather, Garner and his colleagues looked to other options in their study, which involved 36 male and 36 female mice of three common strains. The researchers created sets of two cages linked by a small tube so the mice could move between them. One cage in each set was maintained at a chilly 20 degrees C (68 degrees F) and was equipped with varying quantities of shredded paper, which the animals could use to construct nests for shelter and warmth. The other cage was kept at one of six temperatures: 20, 23, 26, 29, 32 or 35 degrees C (68, 73, 79, 84, 90 or 95 F), but without nesting material.
The mice then had the choice of staying put and tolerating the cold, choosing a balmier cage, eating more to add fat and elevate metabolic rate, or building a nest.
Each strain and sex had slightly different preferences, the researchers found. None was content to simply sit out the cold, either moving to a toastier location, if available, or building elaborate, dome-like nests to warm themselves. The more nest-building material they had, the more they were willing to settle for a cooler clime, as the nests served to temper the chill, the researchers found.
In fact, the nest-building drive was so strong that the mice often would spend hours collecting strands of paper, bit by bit, from the chilliest cage and then transporting it to a more comfortable spot in another cage to build a sturdy little home.
Garner said these mice decided they wanted to have it all, choosing a warm spot and building a nest as well. "Naughty little rascals" is how he described them. "They would go on holiday somewhere warm AND take their nest with them," he said. "Some people like to take a pillow on holiday and some don't. These mice were packing their own pillow."
The fact that some mice moved nesting material to the warmer cage means that the nests serve a function beyond warmth, argued Garner, perhaps providing physical comfort, or a form of protection that decreases the animals' anxiety and stress levels.
The nest-building mice tended to eat less, as they didn't need the extra calories to satisfy their higher metabolic demands, the researchers found. In general, the females preferred warmer temperatures than the males -- by about 5 degrees: they are smaller and have less fat to generate heat.
The researchers concluded that the mice could manage with 6 grams of nesting material but sometimes could use as much as 10 grams, suggesting the larger amount be supplied routinely in research labs.
Another benefit of the nests is that they facilitate researchers' work with the mice -- it's easier to pick them up as well as observe them. "The shape of the nest tells an experienced person whether the animals are too hot or too cold, whether they are sick or whether they are about to give birth," Garner said. "Once you learn how to 'speak mouse nest,' the nest is a wonderful tool that anyone can use to assess the general state of the mouse."

**Published in "SCIENCE DAILY"

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Joseph Garner and his collaborators found that giving lab mice nesting materials helps them naturally regulate their body temperatures at comfortable levels. (Credit: Brianna Gaskill)