CancerWorld

Stop excluding male patients

Fatima Cardoso

Male breast cancer is a rare disease, accounting for less than 1% of all breast cancers worldwide. According to the American Cancer Society, last year it was expected that around 1910 men would be diagnosed with breast cancer in the US with around 440 deaths, compared with around 192,370 expected new cases and 40,170 deaths among women. Male breast cancer patients go through their difficult fight with very little support, while having to cope with the additional stigma of having a ‘female disease’. They also suffer from a lack of evidence on how best to manage their disease. Not a single randomised phase III trial has ever been concluded on male breast cancer. As a consequence, management of male breast cancer is mainly done by extrapolation from its female counterpart. The Breast International Group and the North American Breast Cancer Groups have now joined forces to launch a three-part international research programme for male breast cancer, coordinated by the EORTC. It has kicked off with a meta-analysis of clinical data and a central pathology review of tumour specimens from about 1700 male breast cancer cases diagnosed in participating institutions over the last 20 years. Part 2 of the programme will involve building a prospective international registry of all male breast cancer cases diagnosed at participating institutions over a two-year period, to collect data on demographics, risk factors, treatment and outcomes. Funding is being sought to finance a central analysis of the biological material collected, with a virtual tumour bank being used in the meantime. The intention is to proceed to a randomised clinical trial of endocrine therapy, which could be launched as part 3 of this programme. In view of the failure of all previous attempts to run a clinical trial in this setting, a fully committed international effort will be indispensable. Securing funding for such a non-drug related, purely academic effort has been a daunting process, demonstrating once again the need for a central funding body in Europe. While continuing to look for additional sources of funding, work on the retrospective analysis has already begun thanks to support from the US Breast Cancer Research Foundation which is also funding the BIG--NABCG collaboration that is running the three-part programme [added 02/03/2010]. This research programme could greatly enhance our knowledge of the biology of male breast cancer – an essential first step to guide the development of future therapies. While waiting for the results, a plea is made to all those involved in the design and implementation of breast cancer trials to stop excluding male patients without a good reason. If excluding male patients from endocrine therapy trials may be understandable, excluding them from trials of cytotoxic and biological agents is not. Cancer societies and organisations also need to play their part, by increasing efforts to raise awareness and establish support groups for these patients. Fatima Cardoso is a medical oncologist from the Jules Bordet Institute in Brussels, Belgium, and is the principal investigator of the International Male Breast Cancer Programme. e-mail: Fatima.cardoso@bordet.be

Alain Fourquet: taking multidisciplinarity one step further

Marc Beishon

The importance of a truly multidisciplinary approach to cancer care, though almost universally acknowledged, has yet to be realised in practice outside of the top cancer hospitals. Lack of resources, industry influence, fragmented hospital departments and ascendancy of certain personalities and specialisms – all these play a role in stalling progress. And all are especially apparent in Alain Fourquet’s specialty, radiation oncology, which despite being one of the three central pillars of cancer treatment is often relegated to last place behind medical oncology and surgery. As Fourquet, head of radiation oncology and a specialist in breast cancer and breast conservation at the Curie Institute in Paris notes, it is not just the shortage in many countries of equipment and specialists such as medical physicists and radiographers that accounts for poor recognition of the role of radiation oncology. “One problem is that people are understandably excited about new targeted drugs, but in some of the major trials we are seeing treatments applied without any real evidence of what order and for how long we should be doing things, such as when to give adjuvant chemotherapy and radiotherapy and how to determine efficacy and toxicity. People tend to lack knowledge and expertise in treatments outside their own specialism,” he says. “Another good example is the trend to implement partial breast irradiation in some countries, such as the US. We don’t know whether it is effective – there is no proper science behind it. The history of cancer treatment and breast cancer in particular is that you cannot decide quickly on the effectiveness of new treatments – it can lead to much frustration and misleading conclusions.” And failure to integrate insight and expertise across the disciplines is behind much of the rush to premature judgements, he adds. Fourquet speaks with the authority of virtually an entire career spent in breast radiation oncology, and with an immense knowledge base on some of the oldest – and tried and tested – techniques. “We know that adjuvant radiotherapy cuts the risk of recurrence of breast cancer by 70%–75%. There are no drugs that do that,” he says. Certainly, if there is one place in Europe where a supportive culture of all disciplines, and radiotherapy in particular, is apparent, it is the Curie Institute – founded by one of the most famous scientists, radiation pioneer Marie Curie, and a clinician, Claudius Regaud. “Adjuvant radiotherapy cuts the recurrence of breast cancer by 70%–75%. There are no drugs that do that” “Of course, radiotherapy along with surgery were for many years the only options for treating cancer before we had chemotherapy,” says Fourquet. “But the Curie and France overall has a particular heritage in using radiation in breast conserving treatment, which actually goes back to the 1950s. When I came here it was standard treatment, but unusual elsewhere. It has been routine in French centres since the early 1970s – and wasn’t recommended in the US until the end of the 1980s.” Fourquet’s contribution to the field can best be described as steady, if not spectacular, in line with his belief in the importance of applying research over the long term to understand properly the mechanisms involved in certain approaches. Implementing radiotherapy techniques in general has also been a major preoccupation in recent years. With colleagues at the Curie, he has been patiently building up optimal radiation treatment regimens for breast cancer, and now, as department head for all cancer types, he has been bringing in the new technologies that have radically changed radiotherapy – but doing so with caution and a heavy emphasis on training. In addition to clinical work, Fourquet has been instrumental in driving clinical and translational research at the Curie, which is also France’s largest cancer research institute as well as being a comprehensive cancer centre with its own hospital (in fact it has two hospitals now, following a recent merger with Centre René Huguenin, another cancer centre in Paris). “The future clearly lies in gaining a much better understanding of the biology of breast cancer and other tumours, and I think we have the tools now to identify targets not only for drugs but for radiotherapy too.” “I think we have the tools now to identify targets not only for drugs but for radiotherapy too” A case in point is work being carried out by one of his PhD students on genetic profiling of younger women with breast cancer – why they have a higher recurrence rate and the response to radiotherapy. “This is something I’ve had in mind for some time, and was started by my student with colleagues at the National Cancer Institute in Amsterdam, and is continuing here, as we have a large genomic platform. More results will be presented at the European Breast Cancer Conference [EBCC].” Fourquet has a vested interest in publicising the EBCC – he is the chair of this year’s event, although he is not one of Europe’s great meeting attendees. He tends to pick and choose where he travels, and elected not to go to the San Antonio breast meeting last year, for example. “I agreed to take on the EBCC for two reasons. First, it is becoming an important European conference and we need to have events like this here. I don’t see it competing with the US and it has a wider multidisciplinary emphasis. And second, as far as I know, there has not been a radiation oncologist in the chair until now.” “I don’t see EBCC competing with the US, and it has a wider multidisciplinary emphasis” With colleagues, Fourquet has shortened the conference to three and a half days – it was too long before, he says – and he is injecting more practical debate on clinical cases and controversies, along with the traditional coverage of both clinical and research topics across the breast cancer spectrum. “We have kept the format of parallel sessions and coverage of organisational and political issues as well. Of course we need to balance all interests, with the conference being jointly organised by Europa Donna [European Breast Cancer Coalition], EUSOMA [European Society of Breast Cancer Specialists] and the EORTC (European Organisation for Research and Treatment of Cancer].” As for the profile of radiation oncology at this year’s EBCC, it’s no accident that among a good showing for the field the keynote Emmanuel van der Schueren lecture will be on ‘Research progress and priorities in breast radiotherapy,’ to be delivered by John Yarnold, a clinical oncologist at the Royal Marsden in London. Fourquet knew he wanted to be a doctor from an early age, and went to medical school in Paris. But like many, his choice of specialism came by chance. “I was interested in oncology and haematology, and an opportunity came to work at the Curie, where the director was then Robert Calle, one of the pioneers of breast conservation.” He obtained a resident’s post and has never really looked back. Although some other cancer sites formed parts of his early work, such as lymphomas and Hodgkin’s disease, he moved rapidly into breast, becoming head of the radiation oncology breast cancer service by 1991, and chairman of the entire department by 2006. “I did though spend a year on a fellowship at the Memorial Sloan-Kettering in New York, working with Samuel Hellman, who was one of the first in the US to report breast conserving treatment. I was very close to him. He is a great physician and a dedicated scientist, and was an example for many of my generation. He encouraged me to build up a long-term research programme, which we have done.” But it has not been easy to build up translational research, in particular. “It wasn’t very popular with the biologists here at first, but we now have several translational programmes in my field.” The Curie Institute is now the largest cancer research centre in France, working to an international level in many fields. Recent additions include a developmental biology and cancer centre, opened in 2008. The Curie, he adds, has been rather slow to publicise its achievements and scale – most in the cancer community would cite the Gustave Roussy Institute in the Paris suburb of Villejuif as France’s premier cancer centre. “They have been more active with their PR – but we will be launching a new website this year with a special breast cancer focus that will highlight our achievements and facilities much better,” he says. Apart from the main research and hospital location in central Paris, the Curie also has labs in the suburb of Orsay, and based there is one of only two proton therapy machines in France (the other is in Nice). “Then with the merger with Centre René Huguenin we will go up to 3000 breast cancer patients a year, from 1700,” says Fourquet, “and we aim to have one in five patients for all tumours in clinical trials.” It is a substantial operation, and he also emphasises that the Curie has not only some of the most modern treatment technologies and research platforms, but also the databases and experience, in breast cancer in particular, going back decades, which are proving valuable for research. One key finding has been fundamental to promoting the benefits of radiotherapy. “We have been able to demonstrate that radiation for breast cancer not only has an impact on local control and helps preserve the breast in good condition, but also has an impact on survival, independent of other treatments, which has come recently from statistical overviews such as that by the Oxford Group under Richard Peto. Properly doing our radiation treatment has a secondary impact on distant metastases and cuts long-term mortality.” As he adds, “We were not able to show this for a long time, because the way radiotherapy was delivered 20 to 30 years ago introduced sequelae and long-term complications, and even radiation-related mortality. That’s not the case anymore – we can spare the toxicity and see the long-term impact. Here, we now offer radiotherapy to 85% of women operated on for breast cancer, which is not the case everywhere, although that’s partly due to lack of access to facilities.” That radiotherapy technology has moved on recently is an understatement. As Fourquet notes, the key linear accelerator (linac) machines have not only become much smaller and more reliable, but also radically improved with techniques such as IMRT (intensity-modulated radiotherapy) and integration with sophisticated imaging. “The machines we use now can provide different photon energies for varying the dose, and the combination of imaging and IMRT means that rather than giving a homogeneous dose to one region we can adapt to the anatomy or shape of a tumour. The first big step was 3D conformational targeting and also being able to measure the actual dose in a [tumour] volume and organs at risk, which we couldn’t do before.” The Curie, he adds, was one of the first in Europe to install a tomotherapy machine, which has a CT scanner and linac built into a circular head and allows modulated doses to be delivered at any angle, with the patient on a moving table. “We can really focus treatment on complicated volumes with this, such as being able to spare salivary glands almost completely when treating head and neck cancer – it’s better than what is now conventional IMRT.” He stresses, though, that the aim is to have a ‘one stop shop’ for all radiotherapy options – simple machines are fine for some treatments, such as skin cancer – and with the proton facility and a large number of different machines at the main institute (there are seven linac suites alone), he feels this aim will be achieved with the delivery of a new proton machine, expected this April, which will replace an outdated unit. “In patients with melanoma of the eye, we can achieve about 95% local control with protons. We are aiming especially to treat more children with proton therapy, which will help to cut the long-term risk of contracting other cancers later in life.” “We aim to treat more children with proton therapy,which will cut the risk of other cancers later in life” A major problem is the sheer complexity of the new technologies. “It has been like moving from a single-seater plane to an Airbus – we have many more controls and verification systems, as sources of error are now everywhere. It’s very demanding in terms of training and awareness and we have to be extremely cautious.” “It has been like moving from a single-seater plane to an Airbus... sources of error are now everywhere” Fourquet has a small army of physicists, dosimetrists, radiographers and so on in his large department – the simulation and set-up involved in preparing and delivering treatment is very labour intensive and requires extensive knowledge, despite the fact that it is all done on computers. He is mindful that France, like most countries, has had disastrous failures with radiotherapy — as recently as 2007 there was a major scandal when it was revealed that a hospital in Epinal, north east France, had overdosed many patients, some of whom died. “That was a good example of many things you should not do,” says Fourquet. “The second French cancer plan, which was issued recently, addresses quality in radiotherapy with more radiation oncologists and medical physicists, and a minimum number of patients that a centre must see. It also focuses much more on multidisciplinary working and translational research. To my mind it is much better than the first plan, although that did generate investment in more modern facilities across the country.” The new criteria for radiotherapy units include a minimum of 600 patients a year, with two machines in operation to increase ‘up time’. “You cannot have a centre with only one machine any more, which may cause us problems with capacity. We also have big discussions here about whether we should move to publishing outcomes of hospitals as well, as the UK is doing.” The application of radiotherapy in breast cancer has meant applying evidence-based research to counter dogma over the years, says Fourquet, so any new research focus in France’s cancer plan is only to the good. The demonstration of a mortality impact after controlling for factors such as cardiac mortality has itself helped dispel the dogma that came with the chemotherapy era – that breast cancer was metastatic and local treatment could have no impact. “The quality of local treatment actually then declined until we could show its survival impact,” he notes. “We also published one of the first papers on conserving treatment for DCIS [ductal carcinoma in situ – non-invasive cancer]. Back then there was dogma that DCIS was radio-resistant so the whole breast should be removed. We started a prospective database, which now has 30,000 files, and by 1989 we were able to show that treatment with conserving surgery and radiation has a similar rate of recurrence as with invasive cancer. This triggered a lot of studies to understand DCIS.” Then there is ongoing work on younger women at high risk of cancer through the genetic BRCA1/2 mutations. It had been thought that mastectomy is necessary because conserving surgery followed by radiation would be detrimental because of a lack of DNA repair genes, and cancer may be induced. “But we have been able to show, with others, that there are no more recurrences than in those without the mutations. The explanation seems to be that, although these aggressive tumours lack the ability to repair the DNA mutations, they are actually more sensitive to radiation. This is ongoing research and we need more data, but we have good clues now.” Another major study, carried out by Fourquet and colleagues in the EORTC, has shown the benefit of a higher ‘boost’ radiation dose for younger women, and is also the subject of more ongoing trials in France and the Netherlands. At the other end of the age spectrum, he is equally sure that older women deserve the opportunity to have a full range of treatment, including radiotherapy and chemotherapy, provided health assessments show they can tolerate it. “When the UK, for example, decided not to treat women just because they were old back in the 1970s and 80s, the outcomes were terrible. We nearly always offer radiotherapy to older women here, as we know we can also spare the heart and lung, and we have particular regimens for frail patients.” Some oncologists are suggesting now that older women do not need radiotherapy, but as Fourquet points out, “With the benefit of cutting the risk of recurrence by 70%–75%, what threshold do you decide this is useless for any group? Yes, there could be a patient for whom you estimate the risk is 1% over 10 years, so I agree, a drop to 0.3% or so is tiny. But that is not most patients – the only group I can think of are women who have surgery and endocrine treatment – and then the question is: Which is better, a few courses of non-toxic radiotherapy or five or more years of endocrine drugs with potential side-effects?” A trend he is particularly concerned about now is partial breast irradiation. “The idea of treating only part of the breast with radiation came about for a good reason in states such as Louisiana and Texas in the US where access to health facilities can be poor and women often cannot afford to travel long distances for several radiation cycles. Rather than carrying out mastectomies, oncologists wondered if they could preserve the breast and cut the number of radiation cycles.” The first studies with techniques such as brachytherapy (implanted radiation sources) were interesting, he says, and industry then stepped in with many more approaches. In Europe, countries with overstretched radiotherapy units also became interested, in particular the UK, Italy and Hungary. “But we don’t know if it is effective – there is no real science behind the idea of irradiating a smaller volume. There are trials running now that will eventually give an answer, but not after five years, as most recurrences by then are in the initial site. By ten years and beyond we will see if there are differences. What we know from trials such as that carried out by Umberto Veronesi on conserving surgery alone against surgery and whole breast irradiation is that you have three to four times the number of recurrences if you don’t do radiotherapy, and we know in the longer term we see recurrences elsewhere in the breast, even clonal recurrences – the same as the original tumour – far from the initial site.” As he adds, the trials must go on. “But the approach goes against what we have learned about breast cancer – the host, genetic predisposition and precancerous lesions make up the background for developing the disease and the effect of radiation on the whole organ is why it works. There is no logic to applying a small volume of radiation just because you can.” Where multidisciplinarity is becoming especially important now is in untangling the impact of the many combinations of treatment options opening up with targeted agents. The problem is, says Fourquet, that there is sometimes scant regard for designing trials that demonstrate the efficacy/toxicity balance. “In the conventional surgery, chemotherapy, radiotherapy sequence, there can be trials to insert more cycles of chemotherapy, each time postponing radiotherapy, despite the fact we have shown that the interval between surgery and radiotherapy may have an impact on local control. You could make a small gain by adding a chemo cycle and lose it by delaying radiotherapy, and the patients get more treatment for no benefit.” Resources such as Adjuvant! Online also make no mention of radiotherapy, he notes. “You could make a small gain by adding a chemo cycle and lose it by delaying radiotherapy,” Things get more complex with the addition of agents such as Herceptin (trastuzumab), which can improve adjuvant chemotherapy in 20% of patients. “In the first trials it was given differently – in Europe in the large HERA trial it was started after the end of all therapy, including radiotherapy. But in the US, it was started with chemotherapy and continued during radiotherapy – but it was not tested, just decided. Herceptin is known to improve the radiosensitive effect in vitro, the same type of effect we see with anthracyclines and other drugs. It also has potential cardiotoxicity, so giving it at the same time as radiotherapy raises concerns about long-term harm, but this was not tested in any trial. “This is a typical example with new agents – angiogenesis inhibitors such as bevacizumab [Avastin] can be similarly toxic with radiotherapy. We need to be involved to test new compounds for both toxicity and efficacy by coordinating trial design with medical oncologists and industry. It’s too late when the trials are running.” “We must coordinate trial design with medical oncologists and industry. It’s too late when the trials are running” With breast cancer 10-year survival rates up to 85%, and local recurrence at 6% over the same time, it is of course the groups who have high recurrence rates that most concern Fourquet and colleagues, and the need to avoid unnecessary treatment to others. Like many radiation oncologists, he can see the potential to evolve the field into guiding radiation by tumour biology rather than just conventional imaging. “We need to be able to predict the radiosensitivity of tumours, knowing how various subtypes express genes involved in DNA repair. We can also expect to modulate the way we give radiation according to the structure of the tumour, where we could vary treatment depending on which part of it is growing, using functional imaging such as PET. We are already using PET to target volumes in Hodgkin’s disease that spares other tissues. But we need more backing for research into radiobiology and experimental radiotherapy.” Expect many of these themes to be aired at the EBCC, and for radiation oncologists to be pretty visible, such as one of Fourquet’s most well-known and closest colleagues, Harry Bartelink, long the radiation expert at the Amsterdam National Cancer Institute. Fourquet’s wife Nicole is also in medicine, working as a health geographer, and they have three children, one of whom is a biologist, and one grandchild. That no doubt sparks conversation about his main aim – to drive techniques such as gene profiling forward into everyday guidance for radiation. That’s ambition enough he feels, and in any case he can see no reason to leave France’s premier cancer institute. And with Marie Curie’s laboratory preserved in a small museum on the site, there is certainly motivation to build on her legacy.

Neutropenia in cancer patients: risk factors and management

Sue Mayor

The European School of Oncology presents weekly e-grandrounds which offer participants the opportunity to discuss a range of cutting-edge issues, from controversial areas and the latest scientific developments to challenging clinical cases, with leading experts in the field. One of these will be selected for publication in each issue of Cancer World. In this issue, David Dale, of the University of Washington, in Seattle, USA, reviews the risk factors associated with neutropenia in cancer patients treated with chemotherapy, together with management strategies to reduce adverse outcomes. Jeffrey Crawford, of the Duke University Medical Center, in Durham, North Carolina, USA, poses questions that explore the issue further. The presentation is summarised by Susan Mayor. The recorded version of this and other e-grandrounds, together with 15 minutes of discussion, is available at www.e-eso.net/home.do Severe neutropenia places patients at high risk of serious infection. The lower limit of normal blood neutrophil count is approximately 2000/mm3. Counts below this are classified as neutropenia, and graded according to severity. Counts below 500 cells/mm3 are categorised as grade 4, between 500 and 1000 as grade 3, between 1000 and 1500 grade 2, and the least severe – between 1500 and 2000 cells/mm3 – grade 1. Neutropenia increases susceptibility to infection, particularly in cancer patients. We have known since the early 1960s that both duration and severity of neutropenia are factors that lead to febrile neutropenia – fever and infection – in cancer patients. The duration of neutropenia is particularly important in terms of the risk of infections. Some key lessons in the management of febrile neutropenia in cancer patients have been learned since the 1960s. We have learned to anticipate the problem, and to see and evaluate our patients promptly when any sign of an infection occurs. We have learned where to examine the patient, looking particularly at the skin, the mouth, the area around the anus, and the abdomen for signs of infection. A complete blood count should be taken, including white blood cell count (WBC), WBC differential, haemoglobin, haematocrit and platelet count. If there is fever and severe neutropenia, it is essential to start antibiotics promptly. These basic clinical practices are extremely important for the welfare of our patients. For the past few years, I have been working with my colleagues in the ANC (Awareness of Neutropenia in Chemotherapy) study group towards defining as precisely as possible the risk factors associated with infection, fever, reduction in chemotherapy and unfavourable outcomes in cancer treatment. Or, looked at from another perspective, we have been working to identify the factors that lead to a favourable outcome. Risk factors Most clinicians who have been in practice for a long time will have had experiences of patients doing unexpectedly poorly or dying early in cancer treatment. This risk heightens concern about providing good care and emphasises the need to know the landmarks along the way to avoid this very unfavourable outcome. The figure below outlines the factors that are associated with neutropenia in cancer patients as well as the prognostic factors or risk factors for unfavourable outcomes in patients receiving chemotherapy. One of the most important findings made by the ANC study group a few years ago is that the greatest risk of febrile neutropenia in a patient receiving a course of chemotherapy is with the first cycle. The figure below shows the hazard ratio or risk of febrile neutropenia in patients with non-Hodgkin’s lymphoma receiving standard-dose CHOP (cyclophosphamide, adriamycin, vincrinstine and prednisolone) or equivalent chemotherapy. There is a major peak of febrile neutropenia occurring about 10 days into treatment – at the time of maximum neutropenia with these standard drugs. Later cycles tend to be associated with less severe risk of febrile neutropenia. Many factors may account for this observation, including dose reductions and adaptation of the haematopoietic system after an episode of neutropenia. It is important to realise that neutropenia is a predictable result of exposing the haematopoietic system to standard myelotoxic chemotherapy drugs. This pattern of febrile neutropenia peaking in the first cycle of treatment is observed across a wide spectrum of different types of cancer, indicating that it is a general pattern and that great vigilance is required with the first cycle of treatment with myelotoxic agents in all types of cancer. In the course of our research, we looked at risk factors for neutropenia. The figure below shows important and common risk factors, identified using a risk model based on 1246 patients with non-Hodgkin’s lymphoma who were receiving CHOP. The easily identified risk factors, shown here for patients with lymphoma but more generally applicable, are: age, albumin (as a proxy for nutritional status), the intensity of chemotherapy, the starting white blood cell or neutrophil count, and the presence of hepatic disease. The more risk factors, the greater the risk. Being aware of these risk factors helps health professionals to anticipate the problem of febrile neutropenia. Multivariate analysis shows that age is a very important risk factor, and all older cancer patients need to be aware that they are at greater risk of febrile neutropenia when starting chemotherapy, usually not just because of their age but also because of the comorbidities that accompany the ageing process. Mortality, morbidity and costs Patients who have febrile neutropenia that makes them sick enough to be admitted to hospital have a high risk of an unfavourable outcome. A study by Kuderer et al, which looked at more than 40,000 adult cancer patients treated in large US hospitals, found a mortality rate of 9.5% (Cancer 2006, 106:2258). This increased to 21.4% in those with more than one comorbidity. Other risk factors for mortality were fungal infections, sepsis and pneumonia. Mortality is obviously a severe concern, but hospitalisation and prolonged illness also carry major healthcare costs. Myelosuppressive chemo-therapy-induced neutropenia causes a range of problems, including febrile neutropenia and increased risk of severe infection. It also leads to delays in chemotherapy doses and dose reductions. The dose may be reduced either by giving a smaller amount of drug, or by extending the time over which it is given, resulting in a reduction in dose intensity. Both can lead to reduced survival. There are reasonably good data to indicate that dose intensity is very important. The strongest data come from studies in early-stage breast cancer. A retrospective study carried out by Bonadonna et al, following up patients for at least 20 years, showed that relapse-free survival and overall survival decreased in line with chemotherapy dose intensity (NEJM 1995, 332:901–906). Survival in a study by Pfreundschuh and colleagues of patients with non-Hodgkin’s lymphoma (another chemo-therapy-sensitive cancer) showed similar results (Blood 2004, 104:634–641). There may be some cancers where chemotherapy is less effective, but overall it is clear that giving full-dose, or standard-dose, chemotherapy is the way to achieve the best outcome for patients. It is very important to be aware that relative dose intensity (a measure of the delivered dose intensity as a proportion of the standard dose intensity) is often underreported in randomised controlled trials and long-term outcomes are also not reported. However, when data are available, we have found that dose reductions are very common. The strongest data suggest that a reduction in the dose to less than 85% of what would be predicted to be optimal therapy is quite common in many cancers (Dale et al, JNCCN 2003; 1:440-454). A study of breast cancer adjuvant chemotherapy for a large US population showed that around 50% of patients received less than full-dose chemotherapy. This is a concern, and we should aim to optimise therapy by finding ways to give treatment at the dose that has been shown to be effective in randomised trials. Management strategies To reduce the risk of neutropenic events, including infections, and to avoid dose reductions in the course of giving cancer chemo-therapy, our focus has been on prevention. Treatment of patients with febrile neutropenia admitted to hospital has improved modestly over the years, with better supportive care and better antibiotics, but problems remain, and prevention is the most important strategy to reduce the risk of undertreating or infections in the course of giving cancer chemotherapy. There are three approaches: *delay or reduce the drugs *administer prophylactic antibiotics * give haematopoietic growth factors or myeloid growth factors in a prophylactic strategy. Dose reduction There is little or no evidence that using a dose below 85% of that recommended is favourable for any patient group, although it is a common strategy in palliative care to try to maintain a patient’s quality of life and days that they have to live. Prophylactic antibiotics A large randomised trial conducted by Cullen et al., comparing the quinolone antibiotic levofloxacin with placebo in preventing infection associated with cancer chemotherapy in a large and diverse group of patients, mostly with solid tumours, showed that the antibiotic reduced the occurrence of febrile neutropenia. However, it did not reduce deaths (NEJM 2005, 353:988-998). There are several issues associated with this approach, including that the risk of giving prophylactic antibiotics to the large numbers of patients undergoing treatment with cancer chemotherapy may result in the development of resistant organisms that might cause infections later in cancer treatment. A second international study with levofloxacin in patients with cancer and neutropenia, carried out by Bucaneve and co-workers, also showed that it was effective in reducing febrile episodes (relative risk 76%), but there was no significant effect on infectious deaths or overall deaths (NEJM 2005, 353:977–987). The results show the benefits of antibiotics in reducing the number of bacteria in the short term. However, based on clinical experience, this is only a short-term effect, because the body surface is a rich place for bacteria and fungi to grow, and suppressing some organisms enables others to rapidly emerge. Haematopoietic growth factors Haematopoietic growth factors have been a research interest of mine for a long time, both at basic and clinical levels. Colony stimulating factors, or myeloid growth factors, were discovered in the 1960s, utilising a simple Petri dish culture system. Discovering how to grow blood cells in vitro was a dramatic event – very important in the history of haematology and in the development of modern medical oncology. Probably the most important finding in this research was the discovery of the specific factors that regulate haematopoiesis. Out of this work came the drug we call G-CSF – granulocyte colony stimulating factor – which is a relatively small glycoprotein produced in many cell types in the body, in response to a range of stimuli including injury or infection. Over time, it was learned that the levels of G-CSF in the body regulate the production of neutrophils. We now know that levels of G-CSF increase abruptly when a patient develops an infection. However, becoming gradually neutropenic – as occurs with cancer chemotherapy – does not usually cause G-CSF levels to rise until neutrophils have reached a very low level. The problem with the onset of neutropenia after cancer chemotherapy is that the signal to recover neutrophils occurs late, and gradual recovery occurs if you wait for this natural response.This understanding led to the development of an important clinical use of G-CSF as a drug to accelerate neutrophil recovery after chemotherapy. G-CSF has often been compared to GM-CSF – granulocyte-macrophage colony stimulating factor – because it had similar effects in the early studies in the Petri dish model. However, GM-CSF is a distinctly different molecule and is produced by different cells, particularly T-cells and monocytes. Experimental studies have shown that deficiencies of G-CSF cause neutropenia, but deficiencies of GM-CSF do not. GM-CSF is a very different agent biologically, with different clinical effects. G-CSF/filgrastim G-CSF, or filgrastim (a G-CSF analogue), has a helical structure, which gives the molecule its three-dimensional shape, which is key for interacting with its receptor on myeloid cells. G-CSF acts specifically on myeloid cells that have a receptor for the molecule. G-CSF stimulates neutrophil proliferation and accelerates the delivery of neutrophils from the bone marrow into the blood. Normal neutrophil development and deployment occurs at three levels. In the marrow, cells develop from stem cells to mature neutrophils. In the blood, neutrophils flow along with the red cells, but they stick at sites of inflammation. In the tissues, they migrate to fulfil their function in the containment and killing of bacteria and in mounting a response to infection. In studies to understand the role of G-CSF, we gave these agents to healthy young and elderly volunteers. We were interested in the ageing process and whether older people would respond less well. The studies showed that age does not block the response to G-CSF. The bottom line is that a wide range of patients with different comorbidities and varying in many other factors, including age, all respond to G-CSF quite well, if they have haematopoietic cells in their marrow that are capable of responding. An important point in terms of oncology practice is the effect of G-CSF and GM-CSF on marrow transit time. In our studies we looked at how these agents stimulate the flow of cells through the bone marrow. With no drug, the time for production of a neutrophil, from the last stage of dividing cells to a mature neutrophil in the marrow and its entry into the blood, was about six days. Giving G-CSF accelerates the time for maturation of neutrophils and their entry into the blood. We showed that G-CSF can reduce the time for maturation and deployment of neutrophils by about 50%, reducing the time for cells to transit through the marrow to the blood from approximately six to three days. By stimulating neutrophil production and entry into the blood, G-CSF helps to increase the accumulation of these cells at sites of infection and inflammation. Crawford and Trillet-Lenoir and their co-workers were early investigators of G-CSF in cancer chemotherapy; their work emphasises the principles mentioned above. Their reports were the first to demonstrate a reduction in the occurrence of febrile neutropenia in randomised controlled trials (NEJM 1991, 325: 164-170; EJC 1993, 29A:319-324). Their studies showed that G-CSF accelerates neutrophil recovery after chemotherapy; the return of blood neutrophils was much faster in the G-CSF treated patients. In subsequent clinical trials, Timmer-Bonte and others demonstrated the same effects of G-CSF use to prevent febrile neutropenia with less myelotoxic chemotherapy regimens. For example, in the trial by Crawford et al, there was approximately a 60% risk of febrile neutropenia. In the Timmer-Bonte trial, patients had approximately a 30% risk of febrile neutropenia, and G-CSF treatment also reduced this risk by about 50% (Proc ASCO 2004, 23:726). This is such an important development that there have been many efforts to improve on it over the years. The most valuable was the development of the pegylated molecule (pegfilgrastim), adding polyethylene glycol, making the G-CSF molecule bigger and thereby reducing its renal clearance. A clinical trial carried out by Vogel and co-workers showed that using pegfilgrastim in patients who were treated with less intensive chemotherapy and whose risk of febrile neutropenia was only approximately 20% virtually eliminated the risk of febrile neutropenia (JCO 2005, 23:1178-1184). Issues in the use of G-CSF Although these data are very sound and we can rely on them to set the guidelines in cancer practice, many questions remain. These include whether the dose of G-CSF can be reduced, whether there is a difference between G-CSF and pegylated G-CSF, the place of GM-CSF versus G-CSF, and the use of G-CSF with other drugs such as corticosteroids, which also raise neutrophil counts. There are also questions about timing – should we give G-CSF early, late, or for a few days? Many of these questions have general answers, although most have not been subjected to large randomised trials. Because the myeloid growth factors G-CSF and GM-CSF can stimulate proliferation of both the normal and leukaemic cells, researchers and physicians have been concerned about the potential risks associated with their use. Recently the ANC study group performed a meta-analysis to investigate the risk of myelodysplasia and leukaemia associated with the use of G-CSF as part of supportive care for patients receiving cancer chemotherapy. A systematic review of randomised trials compared the outcomes for cancer patients receiving either chemotherapy alone or chemotherapy plus G-CSF. The study showed a small but statistically significant increase in the occurrence of leukaemia in patients who were randomised to receive G-CSF. On the other hand, overall mortality rates were lower in the patients treated with G-CSF. The G-CSF treated patients also receive more chemotherapy – a finding that complicates the interpretation of these data, because many commonly used myelotoxic drugs can cause leukaemia. There are also other limitations that make these data and similar studies difficult to interpret. The trials were obviously not conducted to see whether treatment causes leukaemia; it is only observed as an adverse effect. There were also variations between trials in the way adverse effects were described and how long the patients were followed before the results of the trial were reported. Some of the ‘control’ patients may also have been given G-CSF, if they seemed to need it. This study was presented and discussed at the American Society of Hematology meeting in December 2009. Nevertheless, the increase in leukaemia with G-CSF treatment was about 0.4% and supportive care with G-CSF is associated with an absolute reduction in all-cause mortality of about 3%–4%. ASCO guidelines on the use of white blood cell growth factors recommend that G-CSF should be used when there is a risk of febrile neutropenia of greater than 20%, unless the treatment is symptomatic or palliative, when dose reduction is usually appropriate. The guidelines also say that primary prophylaxis – the use of CSFs for prevention in the first cycle of treatment – should always be considered for older patients, or where the patient’s medical history or other disease characteristics suggest that there is substantial risk of febrile neutropenia. The National Comprehensive Cancer Network (NCCN) CSF guidelines recommend focusing on three aspects of each patient when determining risk for febrile neutropenia: * Patient-related aspects: age, gender, performance and nutritional status, comorbidities, * Treatment-related aspects: neutropenia, drugs – anthracyclines, relative dose intensity, * Cancer-related aspects: some cancers, including haematological malignancies and lung cancer, and all cancers at advanced stage, predispose patients to infections. The NCCN growth factor algorithm for prophylaxis with growth factors addresses whether chemotherapy is curative, intended to prolong survival or to help with symptom management, or palliative. For cases with a >20% risk of febrile neutropenia with chemotherapy, the CSFs have a benefit that should be considered. CSFs should not be used where the estimated risk is less. In summary: * Use G-CSF if there is a high risk of febrile neutropenia (>20%) with curative intent, to prolong survival, to improve quality of life. * Consider G-CSF if risk of febrile neutropenia is 10%–20%. * Do not use G-CSF if risk of febrile neutropenia is <10%. Each patient should be assessed for their risk of febrile neutropenia, and decisions on whether to give CSFs should be based on this risk. Conclusions Neutropenia, febrile neutropenia and reductions in chemotherapy dosing remain serious problems in medical oncology. Delivering chemotherapy at standard doses and on schedule is important in optimising outcomes. There is good physiological and clinical evidence for the use of G-CSF to prevent febrile neutropenia and ameliorate the myelotoxicities of cancer chemotherapy. Evidence-based medicine and clinical guidelines support the use of G-CSF to prevent chemotherapy-induced neutropenia. Prophylactic antibiotics are alternatives to the CSFs. Treatment of febrile neutropenia, when it occurs, requires very careful attention to the patient, prompt antibiotic therapy and good hospital care. Jeffrey Crawford (JC), of the Duke University Medical Center, in Durham, North Carolina, USA, explored some of the issues further with David Dale (DD). JC: Can we generalise that the standard dose of chemotherapy is standard for all patients, or do we need to think about differences in patients in terms of tolerance to chemotherapy? DD: It is important to see the differences between patients and patient groups. Age is a critical differentiating factor: it bundles together comorbidities and many other factors. Patients over the age of 65, or certainly over age 70, should always be considered at risk and therefore potential candidates for some prophylactic strategy. A second differentiating factor is the patient’s blood cell counts. Patients who have evidence of previous haemotoxicity from drugs or disease are at greater risk, particularly if they have a low white cell count or low neutrophil count. The general physical examination and basis blood count also help us to easily identify patients at greater risk of febrile neutropenia and other complications. Another differentiating factor is the specific drug to be given in the planned chemotherapy regimen. This is a complicated area, because there are so many drugs and combinations. The NCCN guidelines (readily available at nccn.org) provide the best information available about relative risk of neutropenia and severe neutropenia with different drugs. JC: Should there be differences in dosing based on different ethnic populations? DD: There are probably ethnic differences, but we do not know very much about them. For example, the African/American population tends to have somewhat lower baseline white blood cell and neutrophil counts than other groups, but seems to tolerate chemotherapy equally well. JC: How should one calculate the dose of chemotherapy for an obese patient? DD: This is another confusing area. We generally use the body surface area or ideal body weight instead of body mass, as the index for dosing, but there is a point at which there is considerable uncertainty. JC: Larger patients tend to be underdosed if you use the ideal body weight rather than the actual body weight when delivering standard chemotherapy doses. Even though they are getting larger total doses, the body surface area corrects for most of that. One of the concerns about the poor outcomes for obese women with adjuvant breast cancer may be that they are relatively underdosed. Some data suggest that they have less neutropenia, so you should at least use the standard of total body weight and surface area in your calculations. There is also literature around about the importance of neutropenia as a surrogate endpoint for chemotherapy effectiveness. There are data on lymphoma and other settings that patients who develop some degree of neutropenia have a better outcome than those who do not. The same has been shown in advanced-stage lung cancer. This gets back to the question, if we could individualise therapy, what would be the right dose? Presumably what is happening is that there is enough pharmacogenomic variation in how individuals handle drugs that one dose probably does not fit all. But knowing the dose that achieves cytotoxic effect on the patient and that treats their tumour requires further study. JC: Can you comment on the functional effects of G-CSF and GM-CSF? You spoke about neutrophil numbers, but what are the functional effects when these cytokines are active in our bodies? DD: This is a very interesting area. G-CSF has many effects beyond stimulating neutrophil production. It also activates many processes in the cell. For example, it stimulates the formation of the enzymes that go into the granules of neutrophils, particularly the primary granules that are involved with the killing of organisms. G-CSF also ‘primes’ neutrophils, so that they have a greater metabolic burst and greater oxygen and glucose consumption when they are exposed to bacteria or other foreign particles. All of these changes can be seen as part of the host response to infection to enhance the body’s capacity to deal with an infection.